2whf | pdb_00002whf

Interaction of Mycobacterium tuberculosis CYP130 with heterocyclic arylamines

spinqualitylabelsall models 2whf, resolution 1.58Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2whf is a 1 chain structure with sequence from Myctu. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: HEM, II4 Related: 2uvn, 2uuq, 2wgy, 2wh8 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed The Mycobacterium tuberculosis P450 enzymes are of interest for their pharmacological development potential, as evidenced by their susceptibility to inhibition by antifungal azole drugs that normally target sterol 14alpha-demethylase (CYP51). Although antifungal azoles show promise, direct screening of compounds against M. tuberculosis P450 enzymes may identify novel, more potent, and selective inhibitory scaffolds. Here we report that CYP130 from M. tuberculosis has a natural propensity to bind primary arylamines with particular chemical architectures. These compounds were identified via a high throughput screen of CYP130 with a library of synthetic organic molecules. As revealed by subsequent x-ray structure analysis, selected compounds bind in the active site by Fe-coordination and hydrogen bonding of the arylamine group to the carbonyl oxygen of Gly(243). As evidenced by the binding of structural analogs, the primary arylamine group is indispensable, but synergism due to hydrophobic contacts between the rest of the molecule and protein amino acid residues is responsible for a binding affinity comparable with that of the antifungal azole drugs. The topology of the CYP130 active site favors angular coordination of the arylamine group over the orthogonal coordination of azoles. Upon substitution of Gly(243) by an alanine, the binding mode of azoles and some arylamines reverted from type II to type I because of hydrophobic and steric interactions with the alanine side chain. We suggest a role for the conserved Ala(Gly)(243)-Gly(244) motif in the I-helix in modulating both the binding affinity of the axial water ligand and the ligand selectivity of cytochrome P450 enzymes. Interaction of Mycobacterium tuberculosis CYP130 with heterocyclic arylamines.,Podust LM, Ouellet H, von Kries JP, de Montellano PR J Biol Chem. 2009 Sep 11;284(37):25211-9. Epub 2009 Jul 15. PMID:19605350 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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