Atomic Structure of Mycobacterium tuberculosis CYP121 to 1.06 Å Reveals Novel Features of Cytochrome P450
View/ Open
Date
14/02/2003Author
Leys, David
Mowat, Christopher G
McLean, Kirsty J
Richmond, Alison
Chapman, Stephen K
Walkinshaw, Malcolm
Munro, Andrew W
Metadata
Abstract
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.