Structural Analysis of the Streptomyces avermitilis CYP107W1-Oligomycin A Complex and Role of the Tryptophan 178 Residue

Molecules and Cells
Songhee HanDonghak Kim

Abstract

CYP107W1 from Streptomyces avermitilis is a cytochrome P450 enzyme involved in the biosynthesis of macrolide oligomycin A. A previous study reported that CYP107W1 regioselectively hydroxylated C12 of oligomycin C to produce oligomycin A, and the crystal structure of ligand free CYP107W1 was determined. Here, we analyzed the structural properties of the CYP107W1-oligomycin A complex and characterized the functional role of the Trp178 residue in CYP107W1. The crystal structure of the CYP107W1 complex with oligomycin A was determined at a resolution of 2.6 Å. Oligomycin A is bound in the substrate access channel on the upper side of the prosthetic heme mainly by hydrophobic interactions. In particular, the Trp178 residue in the active site intercalates into the large macrolide ring, thereby guiding the substrate into the correct binding orientation for a productive P450 reaction. A Trp178 to Gly mutation resulted in the distortion of binding titration spectra with oligomycin A, whereas binding spectra with azoles were not affected. The Gly178 mutant's catalytic turnover number for the 12-hydroxylation reaction of oligomycin C was highly reduced. These results indicate that Trp178, located in the open pocket of the active site, may...Continue Reading

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Citations

Jun 9, 2016·Trends in Pharmacological Sciences·F Peter GuengerichMartin Egli
Dec 11, 2017·Biomolecules & Therapeutics·Yoon Kyung Choi
Jul 11, 2020·International Journal of Molecular Sciences·Fanele Cabangile MnguniKhajamohiddin Syed
Aug 22, 2020·Archives of Biochemistry and Biophysics·Vitchan KimDonghak Kim

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Software Mentioned

2000
Coot
PyMol
HKL
PRODRG2
Molrep

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