7F0C

Crystal structure of capreomycin phosphotransferase in complex with CMN IIA

Summary for 7F0C

• Entry DOI: 10.2210/pdb7f0c/pdb
• Related PRD ID: PRD_000193
• Descriptor: Capreomycin phosphotransferase, DPP-SER-DPP-UAL-MYN-KBE (3 entities in total)
• Functional Keywords: cph, phosphotransferase, capreomycin, resistance, transferase
• Biological source: Saccharothrix mutabilis subsp. capreolus (Streptomyces capreolus); More
• Total number of polymer chains: 2
• Total formula weight: 32123.18

Authors

Chang, C.Y.,Pan, Y.C.,Wang, Y.L.,Toh, S.I. (deposition date: 2021-06-03, release date: 2022-05-11, Last modification date: 2023-11-29)

Primary citation

Pan, Y.C.,Wang, Y.L.,Toh, S.I.,Hsu, N.S.,Lin, K.H.,Xu, Z.,Huang, S.C.,Wu, T.K.,Li, T.L.,Chang, C.Y.
Dual-Mechanism Confers Self-Resistance to the Antituberculosis Antibiotic Capreomycin.
Acs Chem.Biol., 17:138-146, 2022

PubMed Abstract: Capreomycin (CMN) is an important second-line antituberculosis antibiotic isolated from subspecies . The gene cluster for CMN biosynthesis has been identified and sequenced, wherein the gene was annotated as a phosphotransferase likely engaging in self-resistance. Previous studies reported that Cph inactivates two CMNs, CMN IA and IIA, by phosphorylation. We, herein, report that (1) harboring the gene becomes resistant to both CMN IIA and IIB, (2) phylogenetic analysis regroups Cph to a new clade in the phosphotransferase protein family, (3) Cph shares a three-dimensional structure akin to the aminoglycoside phosphotransferases with a high binding affinity () to both CMN IIA and IIB at micromolar levels, and (4) Cph utilizes either ATP or GTP as a phosphate group donor transferring its γ-phosphate to the hydroxyl group of CMN IIA. Until now, Cph and Vph (viomycin phosphotransferase) are the only two known enzymes inactivating peptide-based antibiotics through phosphorylation. Our biochemical characterization and structural determination conclude that Cph confers the gene-carrying species resistance to CMN by means of either chemical modification or physical sequestration, a naturally manifested belt and braces strategy. These findings add a new chapter into the self-resistance of bioactive natural products, which is often overlooked while designing new bioactive molecules.

PubMed: 34994196
DOI: 10.1021/acschembio.1c00799

Experimental method

X-RAY DIFFRACTION (2.07 Å)