The overall mission of the TB Structural Genomics Consortium is to determine the three-dimensional structures of proteins from M. tuberculosis (Mtb), prioritized by their relevance for drug discovery. Mtb, the causative agent of tuberculosis, remains a major-health threat worldwide, and structural information on relevant proteins is critically needed to support future drug discovery. Our Program Project focuses not only on solving structures of proteins in vulnerable pathways, but also complexes of drug targets with inhibitors bound, which will yield important insights about active-site interactions for drug design. Each of the four projects has chosen to focus on targets and processes that are essential to survival in the host. Project 1 (UCB: PI: Alber) is focused on defining new mechanistic paradigms to Mtb cell-wall biosynthesis and remodeling processes that are essential for cell growth and division. Project 2 (TAMU: PI: Sacchettini) will solve the crystal structures of core metabolic enzymes, including those involved in energy production, biosynthesis of amino acids and co-factors, and biosynthesis of lipid components of the cell wall. Project 3 (UCLA: Pi: Eisenberg) will investigate structures of families of protein complexes, including PE/PPE and ESX proteins, as well as toxin/anti-toxin pairs. Project 4 (UCI, PI: Goulding) will focus on structural characterization of proteins involved in metabolite transport and disulfide-bond isomerization. A novel aspect of our approach is the use of the two Core projects to aid our group projects in structure determination and to gain valuable biological information for their targets. Our Structure Determination Core will produce recombinant protein and crystals, and determine their structures through a high-efficiency pipeline. Our Chemical and Genetic Core will use genetic methods to evaluate the essentiality, function, and interactions of individual targets and also conduct HTS to identify small-molecule inhibitors of our targets. The inhibitors will serve as ligands for co-crystallizatin, and will be valuable chemical tools for probing function in cells and validating targets. All of th structural and biochemical data we collect will be provided to the public;to foster future drug discovery efforts in the academic and pharmaceutical industries.

Public Health Relevance

Our goal is to use structural biology and whole-cell and genetic screens to structurally characterize proteins that represent novel drug targets and vulnerabilities in Mtb. This will provide new opportunities for drug discovery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
3P01AI095208-02S1
Application #
8724062
Study Section
Special Emphasis Panel (ZAI1-JKB-M (M1))
Program Officer
Lacourciere, Karen A
Project Start
2012-09-01
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$60,663
Indirect Cost
Name
Texas A&M University
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
078592789
City
College Station
State
TX
Country
United States
Zip Code
77845
Contreras, Heidi; Joens, Matthew S; McMath, Lisa M et al. (2014) Characterization of a Mycobacterium tuberculosis nanocompartment and its potential cargo proteins. J Biol Chem 289:18279-89
Reddy, Manchi C M; Breda, Ardala; Bruning, John B et al. (2014) Structure, activity, and inhibition of the Carboxyltransferase ?-subunit of acetyl coenzyme A carboxylase (AccD6) from Mycobacterium tuberculosis. Antimicrob Agents Chemother 58:6122-32
Baer, Christina E; Iavarone, Anthony T; Alber, Tom et al. (2014) Biochemical and spatial coincidence in the provisional Ser/Thr protein kinase interaction network of Mycobacterium tuberculosis. J Biol Chem 289:20422-33
Layre, Emilie; Lee, Ho Jun; Young, David C et al. (2014) Molecular profiling of Mycobacterium tuberculosis identifies tuberculosinyl nucleoside products of the virulence-associated enzyme Rv3378c. Proc Natl Acad Sci U S A 111:2978-83
Chim, Nicholas; Johnson, Parker M; Goulding, Celia W (2014) Insights into redox sensing metalloproteins in Mycobacterium tuberculosis. J Inorg Biochem 133:118-26
Mavrici, Daniela; Prigozhin, Daniil M; Alber, Tom (2014) Mycobacterium tuberculosis RpfE crystal structure reveals a positively charged catalytic cleft. Protein Sci 23:481-7
Mavrici, Daniela; Marakalala, Mohlopheni J; Holton, James M et al. (2014) Mycobacterium tuberculosis FtsX extracellular domain activates the peptidoglycan hydrolase, RipC. Proc Natl Acad Sci U S A 111:8037-42
Gokulan, Kuppan; O'Leary, Sean E; Russell, William K et al. (2013) Crystal structure of Mycobacterium tuberculosis polyketide synthase 11 (PKS11) reveals intermediates in the synthesis of methyl-branched alkylpyrones. J Biol Chem 288:16484-94
DeJesus, Michael A; Sacchettini, James C; Ioerger, Thomas R (2013) Reannotation of translational start sites in the genome of Mycobacterium tuberculosis. Tuberculosis (Edinb) 93:18-25
Katibah, George E; Lee, Ho Jun; Huizar, John P et al. (2013) tRNA binding, structure, and localization of the human interferon-induced protein IFIT5. Mol Cell 49:743-50

Showing the most recent 10 out of 13 publications