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Papers In Press, published online ahead of print November 14, 2002
Biochemistry Dept., University of Leicester, Leicester LE1 7RH
Corresponding Author: dl37{at}le.ac.uk
The first structure of a P450 to atomic resolution of 1.06 Å has been solved for CYP121 from Mycobacterium tuberculosis. A comparison with P450eryF (CYP107A1) reveals a remarkable overall similarity in fold with major differences residing in active site structural elements. The high resolution obtained allows visualisation 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 (Pro 346) immediately following the heme iron-ligating cysteine (Cys 345). The active site is remarkably rigid in comparison to 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 Arg 386 is located immediately above the heme plane, dominating the local structure. Putative proton relay pathways from protein surface to heme (converging at Ser 279) 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.
J. Biol. Chem, 10.1074/jbc.M209928200
Submitted on September 27, 2002
Revised on October 31, 2002
Accepted on November 14, 2002
Atomic structure of Mycobacterium tuberculosis CYP121 to 1.06 Å reveals novel features of cytochrome P450
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