This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Mycobacterium tuberculosis (Mtb) secretes a wide variety of small molecules essential for virulence, including PDIM, a complex signaling lipid. Remarkably, the synthesis of these compounds is coupled to secretion. The trimeric pores that mediate docking of the synthetic enzymes to the membrane are encoded by a family of 12 homologous MmpL proteins, each composed of ~900 amino acids. The basis for the secretion specificity of each MmpL protein is unknown. We request SSRL time to determine the structure of a proposed docking domain of MmpL7, which binds the polyketide synthase that catalyzes the terminal steps in the synthesis of PDIM precursors. We have generated an optimized, ~30 KDa construct of the MmpL7 docking domain and obtained crystals that we will characterize next week at LBNL. We expect to have crystals by this fall suitable for solving the structure with MAD phasing. The MmpL7 docking domain will reveal for the first time the machinery for coupled synthesis and secretion of small molecules and establish the groundwork to define the basis for the specificity of the MmpL family.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001209-28
Application #
7598235
Study Section
Special Emphasis Panel (ZRG1-BPC-E (40))
Project Start
2007-03-01
Project End
2008-02-29
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
28
Fiscal Year
2007
Total Cost
$199
Indirect Cost
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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