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Crystal structure of substrate free cytochrome P450 NasF5053 from Streptomyces sp. NRRL F-5053Crystal structure of substrate free cytochrome P450 NasF5053 from Streptomyces sp. NRRL F-5053
Structural highlights
Publication Abstract from PubMedBacterial heterodimeric tryptophan-containing diketopiperazines (HTDKPs) are a growing family of bioactive natural products. They are challenging to prepare by chemical routes due to the polycyclic and densely functionalized backbone. Through functional characterization and investigation, we herein identify a family of three related HTDKP-forming cytochrome P450s (NasbB, NasS1868 and NasF5053) and reveal four critical residues (Qln65, Ala86, Ser284 and Val288) that control their regio- and stereo-selectivity to generate diverse dimeric DKP frameworks. Engineering these residues can alter the specificities of the enzymes to produce diverse frameworks. Determining the crystal structures (1.70-1.47 A) of NasF5053 (ligand-free and substrate-bound NasF5053 and its Q65I-A86G and S284A-V288A mutants) and molecular dynamics simulation finally elucidate the specificity-conferring mechanism of these residues. Our results provide a clear molecular and mechanistic basis into this family of HTDKP-forming P450s, laying a solid foundation for rapid access to the molecular diversity of HTDKP frameworks through rational engineering of the P450s. Molecular basis of regio- and stereo-specificity in biosynthesis of bacterial heterodimeric diketopiperazines.,Sun C, Luo Z, Zhang W, Tian W, Peng H, Lin Z, Deng Z, Kobe B, Jia X, Qu X Nat Commun. 2020 Dec 7;11(1):6251. doi: 10.1038/s41467-020-20022-5. PMID:33288748[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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