2WM4: X-ray structure of Mycobacterium tuberculosis cytochrome P450 CYP124 in complex with phytanic acid

Citation:
Abstract
Mycobacterium tuberculosis (Mtb) produces a variety of methyl-branched lipids that serve important functions, including modulating the immune response during pathogenesis and contributing to a robust cell wall that is impermeable to many chemical agents. Here, we report characterization of Mtb CYP124 (Rv2266) that includes demonstration of preferential oxidation of methyl-branched lipids. Spectrophotometric titrations and analysis of reaction products indicate that CYP124 tightly binds and hydroxylates these substrates at the chemically disfavored omega-position. We also report X-ray crystal structures of the ligand-free and phytanic acid-bound protein at a resolution of 1.5 A and 2.1 A, respectively, which provide structural insights into a cytochrome P450 with predominant omega-hydroxylase activity. The structures of ligand-free and substrate-bound CYP124 reveal several differences induced by substrate binding, including reorganization of the I helix and closure of the active site by elements of the F, G, and D helices that bind the substrate and exclude solvent from the hydrophobic active site cavity. The observed regiospecific catalytic activity suggests roles of CYP124 in the physiological oxidation of relevant Mtb methyl-branched lipids. The enzymatic specificity and structures reported here provide a scaffold for the design and testing of specific inhibitors of CYP124.
PDB ID: 2WM4Download
MMDB ID: 77119
PDB Deposition Date: 2009/6/30
Updated in MMDB: 2011/12
Experimental Method:
x-ray diffraction
Resolution: 2.11  Å
Source Organism:
Similar Structures:
Biological Unit for 2WM4: monomeric; determined by author and by software (PQS)
Molecular Components in 2WM4
Label Count Molecule
Protein (1 molecule)
1
Putative Cytochrome P450 124
Molecule annotation
Chemicals (3 molecules)
1
1
2
1
3
1
* Click molecule labels to explore molecular sequence information.

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