Thomas C. Terwilliger
Bioscience Division, Mail Stop M888, Los Alamos National Laboratory, Los Alamos, NM 87545
Tel.: (505) 667-0072 Email: terwilliger@lanl.gov
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Structural biology research interests
Structural Genomics
Proteins are the molecular machines of life, and a knowledge of their three-dimensional structures is crucial for understanding how they work. A main focus of our laboratory is determining and analyzing the structures of proteins. Our group, along with structural biologists around the world, recognized in the late 1990s that a large-scale effort to determine structures of thousands of proteins could have a profound effect on the understanding of biology. The U.S. Department of Energy and later the National Institutes of Health (the NIH Protein Structure Initiative) have funded our Los Alamos structural genomics team and others around the US to develop and apply technologies for large-scale structure determination. Structural genomics has become a major worldwide effort, and in 2001 our group helped found the International Structural Genomics Organization (ISGO) in order to promote international cooperation in structural genomics.
The TB Structural Genomics Consortium (TB SGC)
The TB Structural Genomics Consortium is a worldwide consortium of hundreds of scientists from around the world devoted to determining structures of proteins from the pathogenic organism M. tuberculosis. Our group founded and led the TB SGC for its first 5 years as part of phase 1 of the NIH Protein Structure Initiative. Now the TB SGC continues as an NIAID-funded project led by Texas A&M University. Los Alamos remains an active member of the TB SGC, operating a Cloning and Protein Production Facility and an X-ray Data collection Facility for the Consortium, and determining structures of proteins from M. tuberculosis. The TB Structural Genomics Consortium has solved over a hundred structures of M. tuberculosis proteins already. We hope that these structures will form a foundation for drug discovery that will lead to improved anti-TB therapy.
The Integrated Center for Structure and Function Innovation (ISFI)
Our Los Alamos group leads the ISFI, a consortium of scientists developing methods for determining protein structures reliably and rapidly. The ISFI is part of phase II of the NIH Protein Structure Initiative. The focus of the ISFI is on development of technologies. Some of our technologies are described on our ISFI web site, and include expression of proteins in a soluble form suitable for structure determination (led by Geoffrey Waldo at Los Alamos), optimization of proteins for crystallization by surface entropy reduction (led by Zygmunt Derewenda at the University of Virginia), improvement of protein crystallization by binding of crystallization chaperones (led by Anthony Kossiakoff at the University of Chicago), determination of structures of protein complexes (led by David Eisenberg at UCLA), and application of these technologies in a pipeline for structure determination including a Cloning and Protein Production facility (led by Chang Kim at Los Alamos), a Crystallization facility (led by Brent Segelke at Lawrence Livermore National Laboratory) and an X-ray Data Collection and Analysis facility (led by Li-Wei Hung at Los Alamos and Lawrence Berkeley National Laboratory).
Methods development for macromolecular crystallography
Our group and our colleagues have developed algorithms and software for analyzing X-ray diffraction data from macromolecules such as proteins and nucleic acids and determining their 3-dimensional structures. Our SOLVE software identifies the locations of heavy-atoms in a crystal and produces a 3-D picture of the molecule. Our RESOLVE software uses advanced algorithms to improve the quality of the image of the molecule and interprets the image in terms of a molecular model. See the SOLVE/RESOLVE home page for many examples and instructions on how to use this software.
Our group is part of the collaborative PHENIX project, an effort led by Paul Adams at LBL that is producing a comprehensive software package for macromolecular structure determination. The PHENIX package includes my SOLVE/RESOLVE software as well as many additional powerful algorithms, including maximum-likelihood molecular replacement (Randy Read's Phaser software), full maximum-likelihood refinement (Paul Adams, Ralf Grosse-Kunstleve, and Pavel Afonine's phenix.refine), and many other useful tools. The PHENIX software is available free for academic users.
The Los Alamos Structural Genomics team
(Phone numbers and emails available using the LANL Directory)
Tom Terwilliger (Los Alamos Structural genomics team leader, terwilliger@LANL.gov)
Technology Development
(see http://www.lanl.gov/source/projects/gfp/ for details about GFP reporter systems)
Geoffrey Waldo (Technology Development Team leader)
Stephanie Cabantous
Jean-Denis Pedelacq
Pawel Listwan
Carolyn Bell
Hau Nguyen
Meghan Lockard
Cloning and Protein Production
Chang-Yub Kim ( Cloning and Protein Production team leader)
Emily Alipio
Heungbok Kim
Xiaohong Shen
X-ray Data Collection and Analysis (ALS; Lawrence Berkeley National Laboratory)
Li-Wei Hung (X-ray Data Collection and Analysis team leader)
Min-Min Yu
Jeff Habel