4C6W: Crystal Structure Of M. Tuberculosis C171q Kasa

Citation:
Abstract
The survival of Mycobacterium tuberculosis depends on mycolic acids, very long alpha-alkyl-beta-hydroxy fatty acids comprising 60-90 carbon atoms. However, despite considerable efforts, little is known about how enzymes involved in mycolic acid biosynthesis recognize and bind their hydrophobic fatty acyl substrates. The condensing enzyme KasA is pivotal for the synthesis of very long (C38-42) fatty acids, the precursors of mycolic acids. To probe the mechanism of substrate and inhibitor recognition by KasA, we determined the structure of this protein in complex with a mycobacterial phospholipid and with several thiolactomycin derivatives that were designed as substrate analogs. Our structures provide consecutive snapshots along the reaction coordinate for the enzyme-catalyzed reaction and support an induced fit mechanism in which a wide cavity is established through the concerted opening of three gatekeeping residues and several alpha-helices. The stepwise characterization of the binding process provides mechanistic insights into the induced fit recognition in this system and serves as an excellent foundation for the development of high affinity KasA inhibitors.
PDB ID: 4C6WDownload
MMDB ID: 114016
PDB Deposition Date: 2013/9/19
Updated in MMDB: 2013/12
Experimental Method:
x-ray diffraction
Resolution: 1.7  Å
Source Organism:
Similar Structures:
Biological Unit for 4C6W: dimeric; determined by author and by software (PISA)
Molecular Components in 4C6W
Label Count Molecule
Proteins (2 molecules)
2
3-oxoacyl-[acyl-carrier-protein] Synthase 1
Molecule annotation
Chemicals (8 molecules)
1
2
2
2
3
1
4
2
5
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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