8HNZ

Crystal structure of cytochrome P450 NasF5053 mutant E73S complexed with 6FCWP

Summary for 8HNZ

• Entry DOI: 10.2210/pdb8hnz/pdb
• Descriptor: Cytochrome P450-F5053, PROTOPORPHYRIN IX CONTAINING FE, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: p450, oxidoreductase
• Biological source: Streptomyces sp. NRRL F-5053
• Total number of polymer chains: 1
• Total formula weight: 44676.24

Authors

Ma, B.D.,Tian, W.,Qu, X.,Kong, X.D. (deposition date: 2022-12-09, release date: 2023-04-19, Last modification date: 2024-05-29)

Primary citation

Sun, C.,Ma, B.D.,Li, G.,Tian, W.,Yang, L.,Peng, H.,Lin, Z.,Deng, Z.,Kong, X.D.,Qu, X.
Engineering the Substrate Specificity of a P450 Dimerase Enables the Collective Biosynthesis of Heterodimeric Tryptophan-Containing Diketopiperazines.
Angew.Chem.Int.Ed.Engl., 62:e202304994-e202304994, 2023

PubMed Abstract: Heterodimeric tryptophan-containing diketopiperazines (HTDKPs) are an important class of bioactive secondary metabolites. Biosynthesis offers a practical opportunity to access their bioactive structural diversity, however, it is restricted by the limited substrate scopes of the HTDKPs-forming P450 dimerases. Herein, by genome mining and investigation of the sequence-product relationships, we unveiled three important residues (F387, F388 and E73) in these P450s that are pivotal for selecting different diketopiperazine (DKP) substrates in the upper binding pocket. Engineering these residues in Nas significantly expanded its substrate specificity and enabled the collective biosynthesis, including 12 self-dimerized and at least 81 cross-dimerized HTDKPs. Structural and molecular dynamics analysis of F387G and E73S revealed that they control the substrate specificity via reducing steric hindrance and regulating substrate tunnels, respectively.

PubMed: 37083030
DOI: 10.1002/anie.202304994

Experimental method

X-RAY DIFFRACTION (1.5 Å)