7F0F

Crystal structure of capreomycin phosphotransferase in complex with CMN IIB

7F0F の概要

• エントリーDOI: 10.2210/pdb7f0f/pdb
• 関連するBIRD辞書のPRD_ID: PRD_002272
• 分子名称: Capreomycin phosphotransferase, DPP-ALA-DPP-UAL-MYN-KBE (3 entities in total)
• 機能のキーワード: cph, phosphotransferase, capreomycin, resistance, transferase
• 由来する生物種: Saccharothrix mutabilis subsp. capreolus (Streptomyces capreolus); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32107.18

構造登録者

Chang, C.Y.,Pan, Y.C.,Wang, Y.L.,Toh, S.I. (登録日: 2021-06-03, 公開日: 2022-05-11, 最終更新日: 2023-11-29)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.1 Å)