Position: Network Coordinator/Researcher
Projects: Structural Neurobiology / Protein Crystallography / Structural Bioinformatics
Personnel
* Dr Gerard J Kleywegt, "Forskare", position funded by SBNet (Network Coordinator)
* Dr Kristina Bäckbro, post-doc, position funded through the Junior Individual Grant
* Emma Jakobsson, MSc student (commences PhD studies in early 1999, funded by SBNet)
Research progress
* Structure determination of monoamine oxidase (MAO). MAO is involved in the biodegradation of aromatic monoamines, including classical neurotransmitters such as serotonin, adrenalin, histamine and dopamine, and appears to play a central role in several psychiatric and neurological disorders (including clinical depression). In February, 1998, Dr Bäckbro visited the laboratory of our collaborator Prof. Creed Abell (Austin, Texas) to get hands-on experience in the isolation and purification of liver MAO-B. Back in Uppsala, she has been working on the purification, but to date we have been unable to obtain sufficient quantities of pure material for crystallisation purposes, mainly due to aggregation problems. In December, we initiated a new collaboration, concerning MAO-A, with the group of Prof. Jean Shih (USC, Los Angeles). She will provide us with pure material, expressed in baculovirus as a His-tagged protein. In 1999, Emma Jakobsson will visit her laboratory to get experience in the expression and purification of this material. In the Autumn, Emma has been working on her MSc project, involving the construction of a homology-based model for MAO. The aim of her study is to investigate if the tendency of MAO to aggregate could be reduced by introducing one or a few mutations, as well as to provide a low-resolution model that could serve as a framework for the interpretation of experimental observations concerning the activity and specificity of MAO-A and B, and possibly the design of new inhibitors.
* Structural and functional studies Inhibitor of Apoptosis Proteins (IAPs). This project is a collaboration with Prof. Dan Lindholm and Dr Alex Mercer (Medical Faculty, UU), and Dr Christina Divne (Biology section, UU). In 1998, we have continued our efforts to try and express several IAP proteins in E. coli, but without positive results. However, the EU has funded an IAP research programme headed by Prof. Lindholm, and a post-doc dedicated to expressing proteins in baculovirus for crystallographic work will start work in January, 1999. We therefore hope and expect to obtain some material suitable for crystallisation during 1999.
* Miscellaneous. Together with Dr Jerry Ståhlberg (SLU), I am working on the structure determination of a CMC-ase from blue mussel. During 1999, I further expect to initiate new protein crystallographic projects in collaboration with Lars Hellman (Biology section, UU).
* Structural Bioinformatics. During 1998, I have completed the development of a set of programs that can be used for the recognition of structural motifs in a large database of protein structures. The program package (SPASM) has been made available to the community, and a paper describing the method and its applications will be published in January, 1999. This project will be continued and expanded over the next two years with support from NFR.
* Morphing. In the autumn of 1998, I developed an algorithm which enables visualisation of conformational changes in macromolecular structures ("morphing"). The method uses chemically reasonable torsional degrees of freedom, which enable one to generate animations that look convincingly "natural". The software is available to the community, and will be incorporated in a WWW-based public morphing server at Yale University.
* Validation. In 1998, I have developed a method which makes it possible to assess differences between models of related macromolecular crystal structures. The unique feature of this method is that it uses experimental crystallographic information, enabling assessment of the extent to which observed structural differences are supported by the experimental data. A manuscript describing the method will be submitted soon. The method builds programs I developed earlier in the year to calculate a density correlation map between different crystal forms or NCS-related copies of a molecule.
* Accuracy in protein crystallography. I have carried out an extensive and careful investigation into the relation between accuracy in protein crystallography and the information provided by various data and model quality statistics. This is the first time that a study of this kind and scale has been carried out. The results, which still await careful analysis and interpretation, refute a number of popular preconceptions and provide experimental support for others.
Miscellaneous events during 1998
* January-February: Principal author of Uppsala's proposal to the SSF to establish a national centre for bioinformatics.
* April: Visited the structural biology department of Pharmacia & Upjohn in Italy, where I gave a series of five seminars.
* May: Organised the Second Annual Conference of the Structural Biology Network, and chaired the session on Bioinformatics.
* May: member of two PhD examination committees, namely for Cristofer Enroth, Karolinska Institute, and Tomas Hansson, Uppsala University.
* June: Organised an SBNet graduate course on the topic of "Protein Structure & Analysis" (23 participants from all over Scandinavia).
* October: Invited to participate in a workshop in Cambridge for protein crystallographic software developers, organised by CCP4 and the EBI.
* October-December: Prof. T.A. Jones and I acted as assessors of the comparative modelling part of CASP3 (community-wide structure prediction effort). For this work, we developed a number of methods that now allow almost fully automated assessment of CASP results. A paper describing the results will be submitted early in 1999.
* December: NFR support obtained for the years 1999 and 2000 for a project in the area of structural bioinformatics.
* December: Principal author of a proposal to the Wallenberg Foundation to support a centre-of-excellence in bioinformatics in Uppsala.
* Refereed 13 papers for Acta Crystallographica, Journal of Molecular Biology, Structure, and FEBS Letters.
* Paper alerts abstracter for the journal Current Opinion in Structural Biology.
* Member of a committee that prepared a proposal to establish a regional centre for High-Performance Computing in Uppsala.
* Siv Andersson (UU), Martin Embley (London), Janet Thornton (London) and I received support from EMBO to organise an international course in bioinformatics in July 1999 (to be held in Uppsala).
* Evil genius behind an April Fools' Day joke that fooled a few hundred seasoned protein crystallographers.
* I continue to maintain three WWW sites with information, software and services relevant to the structural biology community:
* USF, at http://xray.bmc.uu.se/usf/, the Uppsala Software Factory (~20000 visits during 1998, counting only the top page)
* SBNet, at http://xray.bmc.uu.se/sbnet/, the Structural Biology Network (~6000 visits during 1998, counting only the top page)
* HIC-Up, at http://xray.bmc.uu.se/hicup/, the "Hetero-compound Information Centre - Uppsala" (~7500 visits during 1998, counting only the top page)
Publications
G J Kleywegt & T A Jones (1998). Databases in protein crystallography. Acta Cryst. D54, 1119-1131.
G J Kleywegt (1999). Recognition of spatial motifs in protein structures, J. Mol. Biol., in press.
E Karlsson, A L Harvey, C Cerveñansky, G J Kleywegt, M Harel, I Silman & J L Sussman (1999). Fasciculins, cholinesterase inhibitors from mamba venoms. In "Snake Venom Enzymes" (G S Bailey, Ed.), Alaken Inc., Fort Collins (CO), Chapter 21, in press.
B N Chaudhuri, G J Kleywegt, J Björkman, L D Lehman-McKeeman, J D Oliver & T A Jones (1999). The crystal structures of [[alpha]]2u-globulin and its complex with a hyaline droplet inducer. Acta Cryst. D, in press.
G J Kleywegt & T A Jones (1999). Software for handling macromolecular envelopes. Acta Cryst. D, in press.
G J Kleywegt (1999). Structure Validation I. Chapter 21.1, International Tables of Crystallography, Volume F, commissioned.
G J Kleywegt, M Kjeldgaard & T A Jones (1999). O and associated programs. Chapter 25.2.6, International Tables of Crystallography, Volume F, commissioned.
Lectures
* "Refinement and validation of protein crystal structures", lecture in the SBNet graduate course on "Protein Structure & Analysis", Uppsala (S), June 1998.
* Series of five seminars, Pharmacia & Upjohn Italy, Nerviano (I), April 1998.
* "Old gold retold", invited seminar, Department of Medical Biophysics and Biochemistry, Karolinska Institute, Stockholm (S), January 1998.
* "Old gold retold ... and a few new McNuggets", invited lecture, CCP4 Study Weekend "Databases for Macromolecular Crystallographers", Reading (UK), January 1998.
Citations
Citations were counted using ISI's BIBSYS system on 16 December, 1998 (in square brackets are the corresponding counts found one year earlier, on 9 December, 1997). On this date, 43 [39] of my papers had been cited since 1992, with a total of 1134 [752] citations, yielding an impact factor (citations per publication, not corrected for self-citation) of 26 [19].
* In 1993, I published 3 papers that have been cited 217 [168] times to date.
* In 1994, I published 4 papers that have been cited 304 [212] times to date.
* In 1995, I published 5 papers that have been cited 170 [98] times to date.
* In 1996, I published 8 papers that have been cited 202 [79] times to date.
* In 1997, I published 6 papers that have been cited 53 [19] times to date.
Latest update at 18 February, 1999.