2WM4

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

Summary for 2WM4

• Entry DOI: 10.2210/pdb2wm4/pdb
• Related: 2WM5
• Descriptor: PUTATIVE CYTOCHROME P450 124, PROTOPORPHYRIN IX CONTAINING FE, (3R,7S,11S)-3,7,11,15-tetramethylhexadecanoic acid, ... (5 entities in total)
• Functional Keywords: metal-binding, oxidoreductase, omega-hydroxylation, p450, iron, heme, fatty acid, monooxygenase
• Biological source: MYCOBACTERIUM TUBERCULOSIS
• Total number of polymer chains: 1
• Total formula weight: 49808.03

Authors

Johnston, J.B.,Kells, P.M.,Podust, L.M.,Ortiz de Montellano, P.R. (deposition date: 2009-06-30, release date: 2009-10-06, Last modification date: 2023-12-13)

Primary citation

Johnston, J.B.,Kells, P.M.,Podust, L.M.,Ortiz de Montellano, P.R.
Biochemical and structural characterization of CYP124: a methyl-branched lipid omega-hydroxylase from Mycobacterium tuberculosis.
Proc. Natl. Acad. Sci. U.S.A., 106:20687-20692, 2009

PubMed 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.

PubMed: 19933331
DOI: 10.1073/pnas.0907398106

Experimental method

X-RAY DIFFRACTION (2.11 Å)