3CXV
Crystal structure of the Cytochrome P450 CYP121 A233G mutant from Mycobacterium tuberculosis
Summary for 3CXV
| Entry DOI | 10.2210/pdb3cxv/pdb |
| Related | 1N40 2IJ7 3CXX 3CXY 3CXZ 3CY0 3CY1 |
| Descriptor | Cytochrome P450 121, SULFATE ION, PROTOPORPHYRIN IX CONTAINING FE, ... (4 entities in total) |
| Functional Keywords | cytochrome p450, cyp121, mycobacterium tuberculosis, cytoplasm, heme, iron, metal-binding, monooxygenase, oxidoreductase |
| Biological source | Mycobacterium tuberculosis |
| Cellular location | Cytoplasm (By similarity): P0A514 |
| Total number of polymer chains | 1 |
| Total formula weight | 44196.51 |
| Authors | Leys, D. (deposition date: 2008-04-25, release date: 2008-09-23, Last modification date: 2023-08-30) |
| Primary citation | McLean, K.J.,Carroll, P.,Lewis, D.G.,Dunford, A.J.,Seward, H.E.,Neeli, R.,Cheesman, M.R.,Marsollier, L.,Douglas, P.,Smith, W.E.,Rosenkrands, I.,Cole, S.T.,Leys, D.,Parish, T.,Munro, A.W. Characterization of active site structure in CYP121. A cytochrome P450 essential for viability of Mycobacterium tuberculosis H37Rv. J.Biol.Chem., 283:33406-33416, 2008 Cited by PubMed Abstract: Mycobacterium tuberculosis (Mtb) cytochrome P450 gene CYP121 is shown to be essential for viability of the bacterium in vitro by gene knock-out with complementation. Production of CYP121 protein in Mtb cells is demonstrated. Minimum inhibitory concentration values for azole drugs against Mtb H37Rv were determined, the rank order of which correlated well with Kd values for their binding to CYP121. Solution-state spectroscopic, kinetic, and thermodynamic studies and crystal structure determination for a series of CYP121 active site mutants provide further insights into structure and biophysical features of the enzyme. Pro346 was shown to control heme cofactor conformation, whereas Arg386 is a critical determinant of heme potential, with an unprecedented 280-mV increase in heme iron redox potential in a R386L mutant. A homologous Mtb redox partner system was reconstituted and transported electrons faster to CYP121 R386L than to wild type CYP121. Heme potential was not perturbed in a F338H mutant, suggesting that a proposed P450 superfamily-wide role for the phylogenetically conserved phenylalanine in heme thermodynamic regulation is unlikely. Collectively, data point to an important cellular role for CYP121 and highlight its potential as a novel Mtb drug target. PubMed: 18818197DOI: 10.1074/jbc.M802115200 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.7 Å) |
Structure validation
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