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Originally published In Press as doi:10.1074/jbc.M209928200 on November 14, 2002

J. Biol. Chem., Vol. 278, Issue 7, 5141-5147, February 14, 2003
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Atomic Structure of Mycobacterium tuberculosis CYP121 to 1.06 Å Reveals Novel Features of Cytochrome P450*

David LeysDagger §, Christopher G. Mowat||**, Kirsty J. McLeanDagger §, Alison RichmondDagger Dagger , Stephen K. Chapman**, Malcolm D. Walkinshaw||, and Andrew W. MunroDagger §

From the Dagger  Department of Biochemistry, University of Leicester, The Adrian Building, University Road, Leicester LE1 7RH, United Kingdom, the || Structural Biochemistry Group, Institute of Cellular and Molecular Biology, Michael Swann Building, University of Edinburgh, The King's Buildings, West Mains Road, Edinburgh EH9 3JR, United Kingdom, the Dagger Dagger  Department of Pure and Applied Chemistry, University of Strathclyde, The Royal College, 204 George Street, Glasgow G1 1XL, United Kingdom, and the ** Department of Chemistry, University of Edinburgh, The King's Buildings, West Mains Road, Edinburgh EH9 3JJ, United Kingdom

The first structure of a P450 to an atomic resolution of 1.06 Å has been solved for CYP121 from Mycobacterium tuberculosis. A comparison with P450 EryF (CYP107A1) reveals a remarkable overall similarity in fold with major differences residing in active site structural elements. The high resolution obtained allows visualization of several unusual aspects. The heme cofactor is bound in two distinct conformations while being notably kinked in one pyrrole group due to close interaction with the proline residue (Pro346) immediately following the heme iron-ligating cysteine (Cys345). The active site is remarkably rigid in comparison with the remainder of the structure, notwithstanding the large cavity volume of 1350 Å3. The region immediately surrounding the distal water ligand is remarkable in several aspects. Unlike other bacterial P450s, the I helix shows no deformation, similar to mammalian CYP2C5. In addition, the positively charged Arg386 is located immediately above the heme plane, dominating the local structure. Putative proton relay pathways from protein surface to heme (converging at Ser279) are identified. Most interestingly, the electron density indicates weak binding of a dioxygen molecule to the P450. This structure provides a basis for rational design of putative antimycobacterial agents.

* This work was supported by the Biotechnology and Biological Sciences Research Council, Engineering and Physical Sciences Research Council, and European Union (Project "X-TB"). Access at EMBL Hamburg was supported by the European Community-Access to Research Infrastructure Action of the Improving Human Potential Program to the EMBL Hamburg Outstation (Contract HPRI-CT-1999-00017).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and the structure factors (code 1N40 (RCSB017490) and 1N4G (RCSB017506)) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

§ Member of the TB Structural Genomics Consortium.

To whom correspondence should be addressed. Tel.: 44-116-252-3484; Fax: 44-116-252-3473; E-mail: dl37@le.ac.uk.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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