TY - JOUR
T1 - Atomic structure of Mycobacterium tuberculosis CYP121 to 1.06 Å reveals novel features of cytochrome P450
AU - Leys, David
AU - Mowat, Christopher G.
AU - McLean, Kirsty J.
AU - Richmond, Alison
AU - Chapman, Stephen K.
AU - Walkinshaw, Malcolm D.
AU - Munro, Andrew W.
PY - 2003/2/14
Y1 - 2003/2/14
N2 - 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.
AB - 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.
KW - Bacterial Proteins
KW - Cytochrome P-450 Enzyme System
KW - Mycobacterium tuberculosis
KW - Bacteria
KW - Carrier concentration
KW - Conformations
KW - Crystal atomic structure
KW - Protons
UR - http://www.scopus.com/inward/record.url?scp=0038136970&partnerID=8YFLogxK
U2 - 10.1074/jbc.M209928200
DO - 10.1074/jbc.M209928200
M3 - Article
C2 - 12435731
AN - SCOPUS:0038136970
VL - 278
SP - 5141
EP - 5147
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 7
ER -