On-line presentations

Publications
Service
Honors
Background
Grants
Invited Talks

Structural biology current research interests

Phenix: Methods development for macromolecular crystallography

My colleagues and I have developed algorithms and software for analyzing X-ray diffraction and cryo-EM data from macromolecules such as proteins and nucleic acids and determining their 3-dimensional structures. I am part of the collaborative Phenix project, an effort led by Paul Adams at LBL that has produced 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), model improvement and validation (the Richardson laboratory's Molprobity software) and many other useful tools. The Phenix software is available free for academic users.

Many structural biologists are using Phenix to determine structures of coronavirus (SARS-CoV-2) proteins. In the first five months of 2020, 62 structures of SARS-CoV-2 proteins and their complexes with each other, with drugs, and with human proteins were determined using Phenix as part of the process. These include the cryo-EM structure of the drug Remdesivir bound to three SARS-CoV-2 proteins ( the nsp12-nsp7-nsp8 complex bound to the template-primer RNA and triphosphate form of Remdesivir(RTP)), the crystal structure of SARS-CoV-2 receptor binding domain in complex with human antibody CR3022 and the crystal structure of SARS-CoV-2 main protease.

Structural biology recent past research interests

Structural Biology of Bacterial Efflux Pumps

We were part of a multidisciplinary team that focused on understanding how bacteria can pump antibiotics out of the cell and prevent the antibiotics from working. We hope that this understanding may help in developing new drugs that will restore the efficacy of existing antibiotics by blocking these pumps. Our role in this project was to determine structures of the bacterial efflux pumps and their components, focusing on pumps from the pathogenic bacteria Burkholderia pseudomallei but also including other related pumps. As part of this work we determined the structure of an E. coli AcrB pump component bound to the antibiotic Linezolid (Hung et al., 2013).

 
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 has been 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) funded our Los Alamos structural genomics team and others around the US to develop and apply technologies for large-scale structure determination. Structural genomics was a major worldwide from 2001-2015, 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 was a worldwide consortium 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. The TB SGC continued as an NIAID-funded project led by Jim Sacchettini at Texas A&M University. The TB Structural Genomics Consortium solved over a hundred structures of M. tuberculosis proteins and we hope that these structures will form a foundation for drug discovery that will lead to improved anti-TB therapy.