9KLX

The complex structure of XhnM1 and Xinhaicarcin BG

This is a non-PDB format compatible entry.

Summary for 9KLX

• Entry DOI: 10.2210/pdb9klx/pdb
• Descriptor: Class I SAM-dependent methyltransferase, CHLORIDE ION, (S)-N-((2R,3S,3a'R,4R,11'S)-3-((2-amino-6-oxo-1,6-dihydro-7H-purin-7-yl)methyl)-3,7',11'-trihydroxy-5',8'-dioxo-3a',4,5,5',8',9',10',11'-octahydro-3H,3'H-spiro[furan-2,2'-furo[2,3,4-de]naphtho[2,3-h]chromen]-4-yl)-1-methylpiperidine-2-carboxamide, ... (5 entities in total)
• Functional Keywords: methyl group transferase, complex, transferase
• Biological source: Streptomyces xinghaiensis
• Total number of polymer chains: 1
• Total formula weight: 32978.47

Authors

Wu, L.,Tang, G.L. (deposition date: 2024-11-15, release date: 2025-08-20, Last modification date: 2025-12-03)

Primary citation

Nie, Q.Y.,Fang, S.Q.,Wu, L.,Gao, R.Q.,Hu, Y.,Ding, D.,Pan, H.X.,Pei, Z.F.,He, J.B.,Zhou, Q.,Chen, Z.H.,Hou, X.F.,Zhao, X.Q.,Tang, G.L.
Targeted Discovery and Characterization of Type-II PKS-NRPS Hybrid DNA-Alkylating Antibiotics.
Angew.Chem.Int.Ed.Engl., 64:e202512820-e202512820, 2025

PubMed Abstract: DNA alkylating natural products usually exhibit diverse bioactivity and serve as a crucial source of drug leads. Here, we employed genome mining guided by HTH-42 superfamily resistance gene to precisely discover a new class of DNA-alkylating antibiotics, xinghaicarcins, from Streptomyces xinghaiensis. They possess an intricate spiro-epoxide-bearing spiroketal heptacyclic scaffold fused with a pipecolic acid, assembled by a type II polyketide synthase-nonribosomal peptide synthetase hybrid system. An aminotransferase XhnB1 and a methyltransferase XhnM are identified to catalyze the formation of N-methylated pipecolic acid building block, leading to the completion of the polyketide-peptide backbone. The identification of XhnM facilitated stereochemical determination of six chiral centers in xinghaicarcins by co-crystallization. Notably, xinghaicarcins exhibit potent antibacterial activity against drug-resistant pathogens and cytotoxicity against multiple cancer cell lines. Additionally, the HTH-42 superfamily resistant protein, XhnU2, was characterized to mitigate xinghaicarcin-induced genotoxicity. This work provides comprehensive insights into structure, biosynthesis, bioactivity, and self-resistance mechanisms of xinghaicarcins, expanding diversity of DNA alkylating natural products.

PubMed: 40761108
DOI: 10.1002/anie.202512820

Experimental method

X-RAY DIFFRACTION (1.80000915376 Å)