PSI Structural Biology Knowledgebase

PSI | Structural Biology Knowledgebase
Header Icons

id="title" class="nomar"Structures of Mtb Proteins Conferring Susceptibility to Known Mtb Inhibitors

This biological project consists of investigators from Texas A&M University, Los Alamos National Laboratory, and the Harvard School of Public Health. It is partnered with the PSI High-Throughtput Structure Determination center MCSG.

Consortia Investigators

  • Texas A&M University
    James Sacchettini
    Thomas Ioerger
  • Los Alamos National Laboratory
    Thomas Terwilliger
  • Harvard School of Public Health
    Eric Rubin

Contact Information

James Sacchettini
sacchett@tamu.edu

Thomas Terwilliger
terwilliger@lanl.gov

Eric Rubin
erubin@hsph.harvard.edu

Research Description

The overall goal of our center is to identify potential drug targets and companion inhibitors that inhibit growth of Mycobacterium tuberculosis, Pseudomonas aeruginosa and Staphylococcus aureus, in order to develop a foundation for antimicrobial drug discovery against gram positive and gram negative bacteria. Proteins that are targets of inhibitors (e.g. known drugs, or compounds from high-throughput screening) will be identified by genetic and complementary biochemical approaches. Structures will be determined, in collaboration with the Midwest Structural Genomic Consortium, of either the proteins that are targets of inhibitors or close homologs of these proteins. The structural information and inhibitor identities will be used along with annotations of related proteins to suggest molecular functions for each target protein. Assays for these molecular functions will be carried out to confirm both function and inhibition. Once targets are identified, their inhibitors will additionally be analyzed for their activity against other pathogenic bacteria and eukaryotic cell lines. The targets will then be prioritized for struture determination based on their novelty, the spectrum of activity of the companion growth inhibitor and the potency of the inhibitor. These structures, and biochemical information about the proteins will provide a rich resource of lead compounds and biochemistry for drug discovery, a foundation for understanding biology, and a path forward in the effort to improve human health by curing infectious disease.

 

Key Publications
  1. Sassetti, C. M., Boyd, D. H., and Rubin, E. J.
    (2003) Genes required for mycobacterial growth defined by high density mutagenesis

    Mol Microbiol 48,77-84 (DOI: 10.1046/j.1365-2958.2003.03425.x).
  2. Kim, C.-Y., Webster, C., Roberts, J.K.M., Moon, J.H., Alipio Lyon, E. Z., Kim, H., Yu, M., Hung, L.-W., Terwilliger, T.C.
    (1999) Analysis of nucleoside-binding proteins by ligand-specific elution from dye resin: application to Mycobacterium tuberculosis aldehyde dehydrogenases.

    J. Struct. Funct. Genomics 10,291-301 (DOI: 10.1007/s10969-009-9073-z).

Structures, Targets, Publications and Technologies

MTBI Structures in RCSB PDB
MTBI Targets in TargetTrack
MTBI SBKB Publications Page
MTBI SBKB Technology Portal Page

Structural Biology Knowledgebase ISSN: 1758-1338
Funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health