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Crystallography of Molecular Biology: a Report

  E. Majorana Centre, Erice, Trapani, Sicily, Italy: 25 May to 4 June 2000

Since their inception, crystallographic meetings in Erice have striven to explore frontier topics.
Additional photos of Erice and surroundings have been made available by Michael Quayle and Gareth Lewis, Bristol, participants at Erice 1998. 

This event has been divided into two parallel meetings, both sponsored by the International Union of Crystallography and by the International Union of Biochemistry and Molecular Biology, and financed  by Nato under the ASI  Programme.

General outline.

The formal lectures were integrated by several sessions of tutorials and computer demonstrations as organizers were able to rent or use 20 modern PCs and 7 graphic stations offered for the meeting by SiG and Compaq. Eighteen selected "students" were given the occasion to present their work orally and sixtythree could show their results during  poster sessions.

On Sunday 28 the main court of the E. Majorana Centre was named – during a ceremony – in honour of Dorothy C. Hodgkin, Nobel Prize 1964 for Chemistry and in the early years Director of the International School of Crystallography in Erice, who died in 1994. The Erice Vaciago Prize for the most dynamical young (under 35) "student" in the lecture hall was awarded to Bostjan Kobe, Slovenian, working in Australia. A special evening lecture on her May 1999 ten days extraterrestrial flight was given by the canadian astronaut Julie Payette.

Since the fifth crystallographic meeting, 1978, an informal questionnaire is handed to all participants at the end of their stay in Erice ; in June 2000, the question "Would you like to attend a similar meeting in the future?"  resulted in a ratio yes/no 66 to 1 (past averages 10 to 1 !!! ) ;  Erice was indicated as "the" preferred location 90% of the times. The overall figure of merit, expressing satisfaction about every aspect of the meeting, reached the value of 3.18 (maximum 4, minimum 0), the highest ever recorded.

The Course benefited from important financial support from Banco di Sicilia, Sede diTrapani and EMBO, and  from companies  (AstraZeneca, Molndal;  Bristol-Myers Squibb Pharmaceutical Res. Inst., Princeton;    Bruker axs, Karlsruhe;  Compaq Computer Co.,  USA;   Cryosystems, Oxford;   Hampton Research,  Laguna Niguel, CA;   Janssen Pharmaceutica N.V.,  Beerse;  MAR Research, Norderstedt;  Merck & Co. Inc., USA;   Molecular Structure Co.,  USA;  Novartis,  Basel;  Novo Nordisk,  Bagsvaerd;  Pfizer,  Kent;   Pharmacia-Upjohn  Research, Nerviano-Milan;  Roche Discovery,  Welwyn Garden City;   Schering-Plough Res. Inst.,  Kenilworth, NJ).



Methods for Macromolecular Crystallography
Directors : Louise N. Johnson and Dusan Turk

Supported by the EC, DG XII, under Contract No. HPCF-CT - 1999 - 00006 : EuroSummerSchools, the first event of three, short named BIOCRYSTALLOGRAPHY within the series of CrystalSummerSchools>

Crystallisation is a key rate limiting step in the analysis of biological macromolecules by X ray diffraction. Alex McPherson described new approaches to monitoring crystal growth by atomic force microscopy and DeTitta showed quantitative improvements to automate crystal growth - 1536 trials simultaneously – for high throughput structure analysis.

Synchrotron radiation has revolutionised structural biology. The intense source allows data collection from very small samples while the tuneable wavelength has allowed a solution to the phase problem from multi-wavelength anomalous dispersion measurements. Branden gave an overview of macromolecular beam lines world wide (48 total, 20 in Europe and 20 in USA) and demonstrated their important advantages for structural biology and the prospects for the future. Thompson described the experimental set up at synchrotron source for multi-wavelength measurements including the parameters of the synchrotron required, the tuneable wavelength, and the basis of the method for phase determination.

Ealick then took up the theme of detector development, explaining the physical principles behind current detectors. Radiation damage by x-ray radiation previously limited data collection. Garman gave an excellent account of the use of cryomethods (100 °K), that have become so important in the field.

Data processing was admirably covered by Leslie with lectures and by Otwinowski with hands-on computer tutorials in small groups: both practical aspects and considerations about errors - largely appreciated by the younger beginners - that are still problematic were covered.

Phase determination divided into ab initio methods (Sheldrick and Hauptman, a special guest, 1985 Nobel Prize for Chemistry) describing their application when high resolution data (1.2 A) are available and in instances for locating anomalous scatterers applicable at lower resolution (3A). Only 9% of structures solved in 1999 contained a new fold. Navaza and Rossmann described the powerful methods of molecular replacement where an existing structure can be used as a starting point in the interpretation of new structures. This also introduced to the non-crystallographic symmetry averaging and solvent flattening in phase determination. Weckert described the 3-beam method for experimental phasing.

Computer graphic displays and interpretation of electron density maps were covered by Alwyn Jones. Henderson illustrated efficiently the use of electron microscopy to determine structures from 2D arrays. These models are finding increasing application as a starting point for x ray studies of very large structures as exemplified by the work of Stuart and Rossmann. The convergence of X-ray and EM methods was finally thoroughly discussed.

There were 113 scientists, representing 28 nationalities.



Chemical Prospectives in Crystallography of Molecular Biology
Directors : Mariusz Jaskolski and David I Stuart

This ASI was planned in order to give to young scientists the "state of the art" of the Crystallography of Molecular Biology and intended to bring together experimentalists and theoreticians, biochemists, crystallographers and electron microscopists. Advances in macromolecular crystallography have given us new eyes to look at biology. They have led inter alia to an understanding of the rate enhancement of enzyme catalysed reactions, of control of gene expression, of regulation by phosphorylation and by allosteric effectors, of recognition in the component molecules of signal transduction pathways, of recognition in the proteins of the immune response, of energy transduction, of membrane proteins and ion channels, protein/nucleic acid complexes, and of viruses, their assembly from component proteins and their pathogenesis. The most recent results presented by leader scientists in the field gave to the audience the idea of the terrific improvements achieved in the understanding. In addition to the main lectures, young participants had the opportunity to present their results either as oral presentations or as posters.

E. Getzoff (Scripps, USA) excited the audience by illustrating how 0.85 Ĺ resolution crystal structures of the photoactive yellow protein probe the mechanisms of the photocycle on the nanosecond time-scale. This was followed by a series of lectures by participants focusing on recent results with signaling molecules. This theme was further developed by T. Blundell (Cambridge, UK) and J. Kuriyan (Rockefeller University, USA) who showed information on interacting surfaces in molecular recognition (e.g. FGF receptors) and molecular dynamics (e.g. Src kinase) was revealing new biological insights. In the field of immunology, W. Hendrickson (Columbia, USA) talked on the structural biology of HIV envelope glycoproteins and their recognition by immune complexes and D.C. Wiley (Harvard, USA) reviewed how proteins carry out the loading and recognition of peptides on MHC molecules.

The interactions of macromolecules and consequences for biological function was also widely discussed through several examples of structure activity correlations as for example P. Evans (Cambridge, UK) and A. Brunger’s (Yale, USA) contributions on the proteins of endocytosis and exocytosis, respectively and S. Harrison (Harvard, USA) and W. Hol’s (Seattle, USA) talks macromolecular complexes. Membrane proteins have presented difficult problems in view of difficulties in their purification and crystallisation. E. Pebay-Peyroula (Grenoble, France) demonstrated the significant advances made with bacteriorhodopsin crystal structure and C. Hunte (Frankfurt, Germany) demonstrated the success with the very large complex of the yeast cytochrome bc1 complex. Protein nucleic acid interactions are key to understanding the relationship between genes and proteins. T. Richmond (Zurich, Switzerland) described recent results with the nucleosome structure, with regard to understanding the roles of the histone proteins and DNA conformation, and V. Ramakrishnan (Cambridge, UK) described progress with studies on the 30S subunit of the ribosome, showing how the ribosomal proteins decorated the extensive RNA core to form a compact structure.

A session was devoted to the combined utilization of the Electron Microscopy and X-ray Crystallography as synergic tools for improving structural knowledge. This brought together contributions of the experts including A Crowther (Cambridge, UK), K. Downing (Lawrence Berkeley Laboratory, USA) and W. Kuhlbrandt (Frankfurt, Germany). The advantages of combination of X-ray and EM was illustrated in Nobel Laureate Robert Huber’s "EMBO Lecture" on the structures of large protein complexes for protein degradation and protein folding. The potential of the new third generation synchrotron facilities was also presented: their extraordinarily bright beams allow data to be collected from very small crystals. J. Thornton (London, UK) presented an elegant talk on analysis and validation of protein structures illustrating the wealth of information available in the protein structure database and the potential for the future. J Kuriyan (New York, USA) chaired an evening session arranged as a lively round table discussion on the contribution by crystallography to structural genomics.

These achievements are based on many advances in methods and the meeting heard from the experts on the topics of MAD and SAD phasing (W. Hendrickson & A. Brunger), high resolution structures (K. Wilson, York, UK), automatic structure interpretation (T. Terwilliger, Los Alamos, USA and D. Turk, Ljubljana, Slovenia), non-crystallographic averaging, phase combination and choice of coefficients for electron density maps (R. Read, Cambridge, UK), maximum likelihood methods in refinement (E. Dodson, York, UK) and ab initio phasing methods (G. Bricogne, Cambridge, UK). These sessions were followed by hands on tutorials in which participants in small groups had the opportunity to learn first hand from the experts around the computer workstations

There were 114 scientists representing 27 nationalities..

Lodovico Riva di Sanseverino, email, fax +390 51 209 4904