1PKF

Crystal Structure of Epothilone D-bound Cytochrome P450epoK

Summary for 1PKF

• Entry DOI: 10.2210/pdb1pkf/pdb
• Descriptor: cytochrome p450EpoK, PROTOPORPHYRIN IX CONTAINING FE, EPOTHILONE D, ... (4 entities in total)
• Functional Keywords: cytochrome p450epok, oxidoreductase, heme-enzyme
• Biological source: Sorangium cellulosum
• Total number of polymer chains: 1
• Total formula weight: 47931.52

Authors

Nagano, S.,Li, H.,Shimizu, H.,Nishida, C.,Ogura, H.,Ortiz de Montellano, P.R.,Poulos, T.L. (deposition date: 2003-06-05, release date: 2003-10-28, Last modification date: 2024-02-14)

Primary citation

Nagano, S.,Li, H.,Shimizu, H.,Nishida, C.,Ogura, H.,Ortiz de Montellano, P.R.,Poulos, T.L.
Crystal Structures of Epothilone D-bound, Epothilone B-bound, and Substrate-free Forms of Cytochrome P450epoK
J.Biol.Chem., 278:44886-44893, 2003

PubMed Abstract: Epothilones are potential anticancer drugs that stabilize microtubules by binding to tubulin in a manner similar to paclitaxel. Cytochrome P450epoK (P450epoK), a heme containing monooxygenase involved in epothilone biosynthesis in the myxobacterium Sorangium cellulosum, catalyzes the epoxidation of epothilones C and D into epothilones A and B, respectively. The 2.10-, 1.93-, and 2.65-A crystal structures reported here for the epothilone D-bound, epothilone B-bound, and substrate-free forms, respectively, are the first crystal structures of an epothilone-binding protein. Although the substrate for P450epoK is the largest of a P450 whose x-ray structure is known, the structural changes along with substrate binding or product release are very minor and the overall fold is similar to other P450s. The epothilones are positioned with the macrolide ring roughly perpendicular to the heme plane and I helix, and the thiazole moiety provides key interactions that very likely are critical in determining substrate specificity. Interestingly, there are strong parallels between the epothilone/P450epoK and paclitaxel/tubulin interactions. Based on structural similarities, a plausible epothilone tubulin-binding mode is proposed.

PubMed: 12933799
DOI: 10.1074/jbc.M308115200

Experimental method

X-RAY DIFFRACTION (2.1 Å)