Keynotes lectures

Crystal structures of amino acids: investigations into CSD


Prof. Carl Henrik Gørbitz


Department of Chemistry, The Faculty of Mathematics and Natural Sciences, Kjemibygningen, Sem Sælands vei 26, 0371 Oslo, Norway

Monday 24th of August 2015,    8:30 – 9:30 AM

AECC, Hall 5


After the discovery of X-ray diffraction by crystals, amino acids were among the first organic compounds to have their solid state structures investigated. After a short introduction dealing with the early history of crystal structure determination, this keynote will present the main results of a systematic review of more than 3500 entries for alpha-amino acids in the Cambridge Structural Database. This includes an overview of various experimental techniques and conditions, a classification of amino acid structures, and a discussion of their acid-base properties leading to a series of different protonation states. For each such state essential structural elements are described, especially hydrogen bonding preferences and coordination to metal ions. Finally, the concepts of polymorphism and phase transitions as the result of extreme temperatures or pressures are discussed, with reference to recent work.

Chair: Dr Petra Bombicz

Keeping muscle proteins in shape: The moonlighting function of the UNC-45 chaperone


Dr Tim Clausen


Institute of Molecular Pathology (IMP), Dr. Bohr-Gasse 7, 1030 Vienna, Austria

Monday 24th of August 2015,    8:30 – 9:30 AM

AECC, Hall 6


Muscle development and function rely on the correct assembly of contractile units called the sarcomeres. Their main components, thin (actin) and thick (myosin) filaments are organized in a precisely ordered, quasi-crystalline protein framework that mediates muscle contraction. Although the overall architecture of the sarcomere has been studied in detail, little is known about its complicated assembly process. In particular, the mechanism of myosin incorporation into thick filaments is poorly understood.

The UCS (UNC-45/CRO1/She4) chaperones play an evolutionarily conserved role in promoting myosin-dependent processes including cytokinesis, endocytosis, RNA transport and muscle development. To investigate the protein machinery orchestrating myosin folding and assembly, we performed a comprehensive analysis of Caenorhabditis elegans UNC-45. Our structural and biochemical data demonstrate that UNC-45 can form linear protein chains offering multiple binding sites for co-working chaperones and client proteins. Accordingly, Hsp70 and Hsp90, which bind to the TPR domain of UNC-45, could act in concert and with defined periodicity on captured myosin molecules. We thus propose that UNC-45 represents a novel type of filament assembly factor that is capable of coupling myosin folding with myofilament formation.

As for the assembly, also the degradation of muscle myosin is relatively little understood. The U-box containing E3 ligase UFD-2, which is one of the most abundant proteins in embryonic cardiomyocytes, is implicated in this process. New data from our lab reveal the molecular mechanism of UFD-2 in myosin homeostasis. We show that UFD-2 employs UNC-45 as an adaptor protein to target and ubiquitinate the muscle myosin in a highly specific manner. These data suggest that UNC-45 is situated at the interface of myosin folding and degradation pathways. On one side, it interacts with its partner chaperones Hsp70 and Hsp90 to fold and assemble myosin molecules. On the other side, UNC-45 can team up with UFD-2 to ubiquitinate and quality-control damaged myosin proteins. Accordingly, UNC-45 is a central player in the triage system channeling myosin molecules into refolding and ubiquitination pathways, thereby determining the fate of the myosin protein in different cellular situations.

Chair: Dr Kristina Djinović-Carugo

High Pressure Synchrotron Radiation Crystallography, from organic Conductors to Chemistry in the lower Mantle


Dr Michael Hanfland


European Synchrotron Radiation Facility (ESRF), 71, avenue des Martyrs, CS 40220, 38043 Grenoble, France

Monday 24th of August 2015,    5:30 – 6:30 PM

AECC, Hall 5

ID09A is a state of the art high pressure diffraction beamline at the ESRF. It uses monochromatic diffraction with large area detectors. Powder and single crystal diffraction experiments can be performed at high pressures in diamond anvil cells, permitting accurate determination of crystallographic properties of the investigated samples. Soon ID09A will be replaced by a new and improved beamline, ID15B. Recent technical advances have significantly added to the utility of single crystal X-ray diffraction experiments at high pressures [1]. New ways of supporting diamond anvils, like Boehler Almax anvils [2], have considerably increased the volume of accessible reciprocal space. Use of Helium or Neon as pressure transmitting medium extends substantially the practicable pressure range. Flat panel detectors have noticeably decreased the data collection time and increased the accuracy. Data can be collected at low and high temperatures. Even single crystal diffraction experiments with laser heating have become possible [3]. Here we will present several examples to illustrate the recent progress.

Work performed in collaboration with M. Merlini, Universitá degli Studi di Milano, Italy

[1] M. Merlini, M. Hanfland, High Pressure Research 2013 33, 511.

[2] R. Boehler, K. DeHantsetters, High Pressure Research 2004 24, 391.

[3] L. Dubrovinsky, T. Boffa-Ballaran, K. Glazyrin, A. Kurnosov, D. Frost, M. Merlini, M. Hanfland, V.B. Prakapenka, P. Schouwink, T. Pippinger, N. Dubrovinskaia, High Pressure Research 2010 30, 620.

Chair: Dr Yaroslav Filinchuk

Structure and mechanism of respiratory complex I, a giant molecular proton pump


Prof. Leonid Sazanov


Institute of Science and Technology Austria, Klosterneuburg, 3400, Austria

Monday 24th of August 2015,    5:30 – 6:30 PM

AECC, Hall 6


NADH-ubiquinone oxidoreductase (complex I) is the first and largest enzyme in the respiratory chain of mitochondria and many bacteria. It couples electron transfer between NADH and ubiquinone to the translocation of four protons across the membrane. It is a major contributor to the proton flux used for ATP generation in mitochondria, being one of the key enzymes essential for life as we know it. Mutations in complex I lead to the most common human genetic disorders. It is an L-shaped assembly formed by membrane and hydrophilic arms. Mitochondrial complex I consists of 44 subunits of about 1 MDa in total, whilst the prokaryotic enzyme is simpler and generally consists of 14 conserved “core” subunits. We use the bacterial enzyme as a “minimal” model to understand the mechanism of complex I. We have determined the first atomic structures of complex I, starting with the hydrophilic domain, followed by the membrane domain and, finally, the recent structure of the entire Thermus thermophilus complex (536 kDa, 16 subunits, 9 Fe-S clusters, 64 TM helices). Structures suggest an unusual mechanism of coupling between electron transfer in the hydrophilic domain (involving ~ 90 Å long chain of 7 conserved Fe-S clusters) and proton translocation in the membrane domain, via long-range (up to ~200 Å) conformational changes. It resembles a steam engine, with coupling elements (akin to coupling rods) linking parts of this molecular machine. I will discuss our current work, which is aimed at elucidating the molecular details of the coupling mechanism through determination of structures of the complex in different redox states with various bound substrates/inhibitors, using both X-ray crystallography and new cryo-EM methods.

Chair: Prof. Ute Krengel

Evolution of symmetry-broken states in the pseudo-gap regimes of nickelates and cuprates


Dr Emil Bozin


Condensed Matter Physics and Materials Science Department, Brookhaven National Laboratory, Upton, New York 11973, USA

Tuesday 25th of August 2015,    8:30 – 9:30 AM

AECC, Hall 5


Realization that many emerging phenomena, such as colossal magnetoresistance and unconventional superconductivity to name but a few, may be governed by complex disorder exemplifies the importance of utilization of local probes sensitive to short range correlations. To that effect the knowledge of the local atomic structure may reveal relevant nanometer lengthscale footprints important for more comprehensive understanding of the character of symmetry broken states. Atomic pair distribution function (PDF) is one of the few experimental methods that can speak to this problem. Systematic approach in charting both long and short range structural orders, on an equal footing, across the (x, T) phase diagram of materials emerges as a powerful identification tool for grasping the relevance and hierarchy of length scales reflecting competing and/or coexisting orders, such as that seen in e.g. La1-xCaxMnO3.Revealing the nature of the symmetry broken states and fluctuations of short-range order in strongly correlated electron systems in general and in the pseudo-gap (PG) phase of cuprates in particular, remains instrumental in understanding the underlying physical properties.

Mounting experimental evidence suggests that the PG phase of cuprates may represent an electronic state in which the four-fold rotational symmetry (C4) of the CuO2 planes is broken (down to at least C2), pointing to stripe or nematic character. Here the former is referred to as orthogonally equivalent, and the later as orthogonally inequivalent (OI) state. Recent neutron total scattering based results extending the systematic approach to the nickelate and cuprate systems will be presented. In order to benchmark the sensitivity of powder-based methods for this class of problems, we initially explored T-evolution of structural effects associated with the melting of well-established stripe order in La1.67Sr0.33NiO4 across the charge-order temperature, Tco. In this model stripe system structural features sensitive to both long and short range stripe order are identified, further suggesting that dynamic charge-stripe correlations survive to T ~2Tco. Encouraged by these observations, underdoped La2-xBaxCuO4 that hosts stripes was studied next over a range of doping and temperature. PDF and complementary inelastic neutron scattering measurements reveal that dynamic nanoscale OI-type tilt correlations do persist well above Tco and peak  coincidentally near x = 0.125, where stripe order is the strongest.

Chair: Prof. Bogdan Palosz

Structure of a bacterial α-macroglobulin reveals mimicry of eukaryotic innate immunity


Dr Andrea Dessen


Institut de Biologie Structurale (IBS), 71 avenue des Martyrs CS 10090, 38044 Grenoble Cedex 9, France

Tuesday 25th of August 2015,    8:30 – 9:30 AM

AECC, Hall 6

Alpha-2-macroglobulins (A2Ms) are plasma proteins that trap and inhibit a broad range of proteases and are major components of the eukaryotic innate immune system. Surprisingly, A2M-like proteins were identified in pathogenically invasive bacteria and species that colonize higher eukaryotes. Bacterial A2Ms are located in the periplasm where they are believed to provide protection to the cell by trapping external proteases through a covalent interaction with an activated thioester. Our work reveals the crystal structures and characterization of Salmonella typhimurium A2M in different states of thioester activation. The structures reveal thirteen domains whose arrangement displays high similarity to proteins involved in eukaryotic immune defense. A structural lock mechanism maintains the stability of the buried thioester, a requirement for its protease trapping activity. These findings indicate that bacteria have developed a rudimentary innate immune system whose mechanism mimics that of eukaryotes.

Chair: Prof. Adrian Goldman

Solving chemistry puzzles in molecules and crystals through charge and spin density analyses


Dr Carlo Gatti


Institute of Molecular Sciences and Technology, Italian National Research Council (CNR-ISTM), via Golgi 19, 20133 Milan, Italy

Tuesday 25th of August 2015,    5:30 – 6:30 PM

AECC, Hall 5


Being based on a quantum observable and (easily) measurable quantity, the Electron Density (ED) based descriptors retain the great advantage of enabling a comparison of theoretical predictions with experimental results on the same grounds, and regardless of the specific tools used to obtain the observable itself. EDs derived from X-Ray structure factors or from in vacuo and in crystal wavefunctions will be considered during the talk.   On top of customarily used ED topological descriptors [1], this lecture will mostly focus on the Source Function (SF) tool [2,3], and on the Reduced Density Gradient analysis, introduced by Johnson [4] as a convenient instrument to characterize non covalent interactions (NCIs) in vacuo (and recently also made available for [5] and applied to [6-7] NCIs in crystals). The SF enables one to view chemical bonding and other chemical paradigms under a new perspective [3]. Its extension [8] to the electron spin density (ESD) provides special insights on how spin information is transmitted from paramagnetic to non-magnetic centers.   Use of the mentioned ED-based descriptors to help solving chemistry puzzles, like the issue of S hypervalency in the [SO4]2- anion [9], the NC bond length inversion in a thiazete-1,1-dioxide crystal [10], the detection of electron correlation effects [11] and of NCIs nature in molecular organic crystals [5-6] and the distinction of magnetic from relaxation contributions in ESD transmission [8] will be shown.

[1] Modern Charge Density Analysis, C. Gatti and P. Macchi (Eds), Springer  2012

[2] R.F.W. Bader, C. Gatti, Chem. Phys. Lett. 287, 233-238 (1998)

[3]  C. Gatti, Struct. Bond. 147, 193-286 (2012)

[4]  E.R. Johnson et al.  J. Am. Chem. Soc, 132, 6498-6506 (2010)

[5] G. Saleh, L. Lo Presti, C. Gatti, D. Ceresoli, J. Appl Cryst 46, 1513-1517 (2013)

[6] G. Saleh, C. Gatti*, L. Lo Presti * and J. Contreras-García,  Chem. Eur. J., 18, 15523-15536 (2012)

[7] G. Saleh, C. Gatti*, L. Lo Presti* , Comp.Theor. Chem. 998, 148-163 (2012)

[8] C. Gatti, A. M. Orlando, L. Lo Presti,  Chemical Science, 2015, DOI: 10.1039/C4SC03988B

[9] M.S. Schmøkel, S. Cenedese, J. Overgaard, M.R.V. Jørgensen, Y-S Chen, C. Gatti*, Dietmar Stalke,* and Bo B. Iversen*, Inorg. Chem. 51, 8607-8616 (2012)

[10] L. Lo Presti,* A. Orlando, L. Loconte, R. Destro, E. Ortoleva, R. Soave, C. Gatti*,  Cryst. Growth and Design, 14, 4418-4429 (2014)

[11] C. Gatti, G. Saleh, L. Lo Presti, invited feature article to be submitted to Acta Cryst B

Chair: Prof. Anders Østergaard Madsen

Quasicrystals in soft condensed matter


Prof. Ron Lifshitz


Raymond & Beverly Sackler School of Physics & Astronomy, Tel Aviv University, Tel Aviv 69978, Israel

Tuesday 25th of August 2015,    5:30 – 6:30 PM

AECC, Hall 6


Recent years have shown a resurgence of scientific interest in quasicrystals, perhaps amplified by the award of the 2011 Nobel Prize in Chemistry to Dan Shechtman; yet mostly driven by breakthroughs in unlocking their crystal structure [1], and by the expanding scope of the field owing to the advent of a host of new experimental systems exhibiting aperiodic long-range order. Among these are soft-matter quasicrystals whose building blocks—rather than being individual atoms—are composed of large synthesized particles such as macromolecules, block co-polymers, nanoparticles, and colloids [2-5]. At these dimensions it is possible to design the interaction between particles, manipulate their positions, or even artificially place them at pre-assigned locations. It may also be possible to track the dynamics of individual particles, and in the optical domain even observe quantum wave functions. Consequently, these mesoscopic-scale quasicrystals provide rich and versatile platforms for the fundamental study of the basic physics of quasicrystals. At the same time they hold the promise for new applications based on artificial or self-assembled nanomaterials with unique physical properties that take advantage of the lack of periodicity, such as novel photonic metamaterials.

After giving a brief overview of the rapidly expanding field of soft-matter quasicrystals, I shall demonstrate how a quantitative understanding of their thermodynamic stability [6] has given us the ability to control the self-assembly of a variety periodic and aperiodic soft-matter crystals (at the moment only on the computer) and has led to the numerical discovery of a novel phase—a so-called “cluster quasicrystal” [7]. If time permits, I shall describe the design of nonlinear photonic quasicrystals for optical frequency-conversion applications [8].

[1] Takakura, Pay Gomez, Yamamoto, de Boissieu, Tsai (2007) Nature Materials 6, 58.

[2] Zeng, Ungar, Liu, Percec, Dulcey, & Hobbs (2004) Nature 428, 157.

[3] Hayashida, Dotera, Takano, & Matsushita (2007) Phys. Rev. Lett. 98, 195502.

[4] Talapin, Shevchenko, Bodnarchuk, Ye, & Murray (2009) Nature 461, 964.

[5] Mikhael, Roth, Helden, & Bechinger (2008) Nature 454, 501.

[6] Lifshitz & Diamant (2007) Phil. Mag. 87, 3021; Barkan, Diamant, & Lifshitz (2011)  Phys. Rev. B 83, 172201.

[7] Barkan, Engel, & Lifshitz (2014) Phys. Rev. Lett. 113, 098304.

[8] Lifshitz, Arie, & Bahabad (2005) Phys. Rev. Lett. 95, 133901.

Chair: Prof. Janusz Wolny

Crystallographic Studies on Correlated Electron Systems under Non-Ambient Conditions


Dr Karen Friese


Jülich Centre for Neutron Science (JCNS), Forschungszentrum Jülich GmbH, 52425 Jülich, Germany

Wednesday 26th of August 2015,    8:30 – 9:30 AM

AECC, Hall 5

Structural characteristics like symmetry, interatomic distances, or thermal movements of the atoms are closely related to the properties of a material. Correlated electron systems exhibiting novel magnetic properties, a superior optical and electric performance or superconductivity have excellent prospects as advanced materials. However, the establishment of reliable structure/property relationships is often difficult due to complications in the crystal structure determination process. This talk will concentrate on two classes of materials which are characterized by a strong coupling of charge, spin and/or lattice degrees of freedom. The first part will be centered on the behaviour of the crystal and magnetic structures of magnetocaloric compounds. In these materials, which can be used for advanced refrigeration technologies, the application of a magnetic fiels leads to changes in the magnetic entropy and adiabatic temperature. The magnetocaloric transition is usually accompanied by a structural transition and the response of the lattice to the onset of magnetic ordering is of key importance for the understanding of the underlying mechanism of the magnetocaloric effect. The second example will concentrate on mixed-valence compounds. Here, charge ordering can lead to significant changes of the coordination spheres of the aliovalent ions and lead to drastic changes in the underlying crystal structures often reflected in first-order phase transitions. Multiparametric studies on both systems performed at neutron and synchrotron source will be presented. Apart from the variation of temperature and chemical composition, hydrostatic pressure plays a key role in these studies as it permits to drastically influence the interatomic distances in the materials and can thus help to better understand the underlying mechanisms of the observed phenomena.

Chair: Dr Julien Haines

Advanced electron crystallography through imaging


Prof. Sandra Van Aert


Electron Microscopy for Materials Science (EMAT), Universiteit Antwerpen, Groenenborgerlaan 171, 2020 Antwerp, Belgium

Wednesday 26th of August 2015,    8:30 – 9:30 AM

AECC, Hall 6


New developments in the field of nanoscience and nanotechnology drive the need for advanced quantitative materials characterisation techniques that can be applied to complex nanostructures. The physical properties of these nanostructures are controlled by composition and chemical bonding, but also by the positions of the atoms. Indeed, changing the interatomic distances by picometers can turn an insulator into a conductor. Because of the presence of defects, interfaces and surfaces, the locations of atoms deviate from their equilibrium bulk positions giving rise to strain. In order to study nanostructures, transmission electron microscopy (TEM) is an excellent technique because of the strong interaction of electrons with small volumes of matter providing local information on the material under study. Over the past few years, remarkable high-technology developments in the lens design greatly improved the image resolution. Nowadays, a resolution of the order of 50 pm can be achieved. For most atom types, this exceeds the point where the electrostatic potential of the atoms is the limiting factor. Furthermore, new data collection geometries are emerging that allow one to optimise the experimental settings. In addition, detectors behave more and more as ideal quantum detectors. In this manner, the microscope itself becomes less restricting and the quality of the experimental images is mainly set by the unavoidable presence of electron counting noise and environmental disturbances. In order to measure the atom positions and atom types as accurately and precisely as possible from atomic resolution TEM image, quantitative methods are required. To reach this goal, the use of statistical parameter estimation theory is of great help. This methodology allows one to measure 2D atomic column positions with subpicometer precision, to measure compositional changes at interfaces, to count atoms with single atom sensitivity, and to reconstruct 3D atomic structures. Using current state-of-the-art experimental examples, it will be shown how statistical parameter estimation techniques can be used to overcome the traditional limits set by modern TEM. The precision that can be achieved in this quantitative manner far exceeds the resolution performance of the instrument. This opens up a whole new range of possibilities to understand and characterise nanostructures at the atomic level and to help developing innovative materials with revolutionary interesting properties.

Chair: Prof. Xiaodong Zou

Crystallization and Gelation: Orthogonal Self-Assembly Far from Equilibrium


Prof. Jonathan Steed


Department of Chemistry, Durham University, Lower Mountjoy, South Road, Durham DH1 3LE, UK

Wednesday 26th of August 2015,    5:30 – 6:30 PM

AECC, Hall 5


A vast and diverse array of organic compounds and coordination complexes form gels by hierarchical self-assembly either because of hydrophobic effects in water or by more directional interactions such as hydrogen bonding in less polar solvents. Of recent interest is the emergence of metal-, anion and salt-containing gelators based on small-molecule ‘low molecular weight gelators (LMWG). Particular attractions of LMWGs to the scientific community are the reversible nature of the interactions between the gelator molecules, the wide (essentially unlimited) range  of solvents that can be gelled and the possibility of tuning the gels’ behaviour by introducing responsive or switching functionality Gels derived from LMWGs have been proposed in a range of applications and include templation of nanoparticles and nanostructures, drug delivery and as crystal growth media. This presentation focuses on the use of concepts borrowed from anion host-guest chemistry to control and trigger the materials properties of small molecule (supramolecular) gels. We show how concepts firmly rooted in supramolecular host-guest chemistry and supramolecular self-assembly can be married with the materials science of soft matter in order to utilise a molecular-level understanding of supramolecular chemistry to control and manipulate bulk materials properties. This ‘evolution’ has been described in a recent review,1 and the application of these kinds of switchable gels as novel media for pharmaceutical crystal growth has recently been described.2

Steed, J. W. Chem. Soc. Rev. 2010, 39, 3686.

Kumar, D. K.; Steed, J. W. Chem. Soc. Rev. 2014, 43, 2080.

Chair: Prof. Alessia Bacchi

Molecular Structure and Luminescent Properties


Prof. Paul Raithby


University of Bath, Claverton Down, Bath, BA2 7AY, United Kingdom

Wednesday 26th of August 2015,    5:30 – 6:30 PM

AECC, Hall 6


Luminescence can either take the form of fluorescence, emission of a photon from a singlet excited state, or phosphorescence, emission from an excited triplet state.  The fluorescent emission normally occurs on a much faster timescale than phosphorescence. Being able to exploit phosphorescence emission enhances the emission efficiency, since there are three accessible triplet states for each singlet state.  However, in order to achieve this singlet to triplet intersystem crossing has to occur.  This is facilitated by the presence of heavy transition metals, such as osmium, iridium or platinum, with their associated high spin-orbit coupling. Thus, there has been considerable interest in platinum(II) poly-yne complexes and polymers which display excellent phosphorescence properties.  These materials take the form of platinum (II) dimers linked by an aromatic or heteroaromatic linker group, or related polymers (Figure 1a).1  In these systems we have found it possible to tune the electronic band gap, and the luminescent properties, by changing the donor/acceptor properties of the linker group, its length and the properties of auxiliary ligands on the metal centres.2  More recently, we have found that related platinum(II) pincer complexes (Figure 1b) show changes in their colour and luminescent properties depending on how they pack in the solid-state.  This packing, and hence the luminescence, can be modified by the introduction of various solvents and volatile organic compounds into the crystal.  These colour changes occur on a sub-second time scale providing a new class of rapid-acting sensors.

References 1 Chawdhury, N.; et. al.. J. Chem. Phys. 1999, 110 (10), 4963-4970. 2 Devi, L. S.; et. al. Macromolecules 2009, 42 (4), 1131-1141.

Chair: Prof. Alessandra Crispini

Structure determination revisited


Prof. George Sheldrick


Institute of Inorganic Chemistry, Tammannstrasse 4, 37077 Göttingen, Germany

Thursday 27th of August 2015,    8:30 – 9:30 AM

AECC, Hall 5


Recent developments in the experimental phasing of both small and macromolecules with the SHELX programs will be discussed. In both cases the amount of user input required has been reduced to an absolute minimum.

The new program SHELXT (released August 2014)  for small molecule structure solution requires only the unit-cell, Laue group, reflection data and an approximate indication of which elements might be present. The phase problem is solved for data expanded to space group P1 and the resulting phases are then used to determine the true space group. This is much more robust than conventional methods based on systematic absences etc. The integrated electron density enables most elements to be identified correctly.

The programs SHELXC, SHELXD and SHELXE apply the SAD, MAD, SIRAS, SIR and RIP methods for experimental phase determination followed by density modification and iterative poly-alanine tracing. SHELXE may also be used to improve borderline molecular replacement solutions. The statically linked SHELX programs have zero dependencies – no libraries, other programs or environment variabes are required – and are available free for academic use for Windows, Linux and MacOSX systems. Further details may be found on the SHELX homepage.

Chair: Prof. Isabel Usón

Trapping a transient state in DNA mismatch repair: the MutS/MutL sliding clamp loads MutL on DNA


Dr Titia Sixma


Division of Biochemistry Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands

Thursday 27th of August 2015,    8:30 – 9:30 AM

AECC, Hall 6


Flora S. Groothuizen1, Ines Winkler2, Michele Cristóvão2, Alexander Fish1, Herrie H.K. Winterwerp1, Annet Reumer1, Andreas D. Marx2, Nicolaas Hermans3, Robert A. Nicholls4, Garib N. Murshudov4, Joyce H.G. Lebbink3, Peter Friedhoff2, Titia K. Sixma1

1Netherlands Cancer Institute (NKI), Amsterdam, the Netherlands, 2Justus-Liebig-University, Giessen, Germany, 3ErasmusMC, Rotterdam, the Netherlands, 4LMB, Cambridge, UK

To avoid mutations in the genome, DNA replication is followed by DNA mismatch repair (MMR). This process starts when a MutS homolog recognizes a mismatch and undergoes an ATP-dependent transformation to an elusive sliding clamp state. How this transient state promotes MutL homolog recruitment and activation of repair is unclear.

Here we present the crystal structure of the MutS/MutL complex where we trap this transient state, by making use of highly specific single-cysteine crosslinking. The resulting structures (4.7-7.6 Å) have suprisingly large conformational changes that were validated by FRET, binding studies and mutagenesis and interpreted in terms of the MMR cycle.

The structure captures MutS in the sliding clamp conformation, where tilting of the MutS subunits across each other pushes DNA into a new channel, and reorientation of the connector domain creates an interface for MutL with both MutS subunits. Our work explains how the sliding clamp promotes loading of MutL onto DNA, to activate downstream effectors. We thus elucidate a crucial mechanism that ensures that MMR is initiated only after detection of a DNA mismatch.

Chair: Prof. Udo Heinemann

Molecular mechanisms of RNA polymerase I and III transcription


Dr Christoph Müller


European Molecular Biology Laboratory (EMBL) Heidelberg , Meyerhofstraße 1, 69117 Heidelberg, Germany

Thursday 27th of August 2015,    5:30 – 6:30 PM

AECC, Hall 5

RNA polymerase (Pol) I and Pol III mainly synthesize the non-coding RNA components required for ribosome assembly and protein synthesis in eukaryotes. Pol I synthesizes precursor rRNA that is subsequently processed into 25S, 18S and 5.8S rRNA, while Pol III produces small RNAs such as tRNA, 5S RNA and U6 snRNA. The Pol I and Pol III transcription initiation machineries are carefully regulated in healthy cells, while misregulation of Pol I and Pol III transcription is observed in a variety of cancers. Our group uses an integrated structural biology approach combining X-ray crystallography, single-particle electron microscopy and chemical crosslinking mass spectrometry to study the Pol I and Pol III enzymes and their transcription initiation complexes. We have determined the crystal structure of the 14-subunit RNA polymerase I from Saccharomyces cerevisiae at 3.0 Å resolution. The Pol I structure shows a very wide DNA-binding cleft that is occupied by an extended loop mimicking DNA. The Pol I-specific subunits A12.2 and A49-A34.5 provide additional functionality to the enzyme. The crystal structure of Pol I will be compared to the cryo-electron microscopy structure of the 17-subunit Pol III enzyme. Recruitment of Pol III to tRNA-encoding genes requires the general transcription factors (TF) IIIB and IIIC. TFIIIC is a multi-subunit protein composed of two subcomplexes. We used chemical cross-linking mass spectrometry to determine the overall architecture of TFIIIC and to position crystal structures corresponding to about 2/3 of the entire TFIIIC complex.

Chair: Prof. Nenad Ban

Ultrafast dynamics in condensed matter


Prof. Matias Bargheer


Institute of Physics and Astronomy, University of Potsdam, Karl-Liebknecht-Strasse 24/25, 14476 Potsdam, Germany

Thursday 27th of August 2015,    5:30 – 6:30 PM

AECC, Hall 6

This lecture will give an introduction to the field of ultrafast x-ray diffraction (UXRD) and related techniques such as inelastic or diffuse x-ray scattering. Generally, we excite molecules or solids by ultrashort light pulses and monitor the dynamics on the natural timescale of atomic motion, i.e with a resolution of about 100 femtoseconds. The idea is to generate movies that teach us how energy flows in complex material systems. The main body of the lecture will discuss very recent experimental progress in the field using both laser-based plasma x-ray sources and synchrotron radiation. As a tutorial example, we demonstrate how UXRD can monitor the inhomogeneous excitation of metallic thin films and the associated generation of hyper-sound waves. This process is used to tailor giant phonon-wavepackets with a well defined wavevector, although localized to few tens of nanometers. We not only observe the generation and decay of these phonons directly by UXRD. We can even monitor nonlinear phonon-phonon interaction in real time. As a second very recent research area monitors the structural changes of rare earth metals after heating with ultrashort laser pulses. The transient lattice strain can be used as a local ultrafast thermometer, that tells us about the heat flow within a multilayered sample, where a very large fraction of the heat can be trapped in antiferromagnetic excitations (magnons and fluctuations). We discuss the complex lattice dynamics induced by various stress contributions from anharmonic lattice heat expansion to forces induced by the magnetic exchange interaction. In the vicinity of the Neel temperature we observe critical behavior in the observed relaxation timescales that are connected with fluctuations at the phase transition.

Chair: Prof. Ullrich Pietsch