+検索条件
-Structure paper
タイトル | Identifying antibiotics based on structural differences in the conserved allostery from mitochondrial heme-copper oxidases. |
---|---|
ジャーナル・号・ページ | Nat Commun, Vol. 13, Issue 1, Page 7591, Year 2022 |
掲載日 | 2022年12月8日 |
![]() | Yuya Nishida / Sachiko Yanagisawa / Rikuri Morita / Hideki Shigematsu / Kyoko Shinzawa-Itoh / Hitomi Yuki / Satoshi Ogasawara / Ken Shimuta / Takashi Iwamoto / Chisa Nakabayashi / Waka Matsumura / Hisakazu Kato / Chai Gopalasingam / Takemasa Nagao / Tasneem Qaqorh / Yusuke Takahashi / Satoru Yamazaki / Katsumasa Kamiya / Ryuhei Harada / Nobuhiro Mizuno / Hideyuki Takahashi / Yukihiro Akeda / Makoto Ohnishi / Yoshikazu Ishii / Takashi Kumasaka / Takeshi Murata / Kazumasa Muramoto / Takehiko Tosha / Yoshitsugu Shiro / Teruki Honma / Yasuteru Shigeta / Minoru Kubo / Seiji Takashima / Yasunori Shintani / ![]() |
PubMed 要旨 | Antimicrobial resistance (AMR) is a global health problem. Despite the enormous efforts made in the last decade, threats from some species, including drug-resistant Neisseria gonorrhoeae, continue to ...Antimicrobial resistance (AMR) is a global health problem. Despite the enormous efforts made in the last decade, threats from some species, including drug-resistant Neisseria gonorrhoeae, continue to rise and would become untreatable. The development of antibiotics with a different mechanism of action is seriously required. Here, we identified an allosteric inhibitory site buried inside eukaryotic mitochondrial heme-copper oxidases (HCOs), the essential respiratory enzymes for life. The steric conformation around the binding pocket of HCOs is highly conserved among bacteria and eukaryotes, yet the latter has an extra helix. This structural difference in the conserved allostery enabled us to rationally identify bacterial HCO-specific inhibitors: an antibiotic compound against ceftriaxone-resistant Neisseria gonorrhoeae. Molecular dynamics combined with resonance Raman spectroscopy and stopped-flow spectroscopy revealed an allosteric obstruction in the substrate accessing channel as a mechanism of inhibition. Our approach opens fresh avenues in modulating protein functions and broadens our options to overcome AMR. |
![]() | ![]() ![]() ![]() |
手法 | EM (単粒子) / X線回折 |
解像度 | 2.2 - 3.09 Å |
構造データ | EMDB-33293, PDB-7xmc: EMDB-33294, PDB-7xmd: ![]() PDB-7xma: ![]() PDB-7xmb: |
化合物 | ![]() ChemComp-HEA: ![]() ChemComp-CU: ![]() ChemComp-MG: ![]() ChemComp-NA: ![]() ChemComp-PER: ![]() ChemComp-PGV: ![]() ChemComp-TGL: ![]() ChemComp-CUA: ![]() ChemComp-CDL: ![]() ChemComp-CHD: ![]() ChemComp-PEK: ![]() ChemComp-PSC: ![]() ChemComp-ZN: ![]() ChemComp-DMU: ![]() ChemComp-HOH: ![]() ChemComp-J6X: ![]() ChemComp-HEO: ![]() ChemComp-HEM: ![]() ChemComp-PEE: ![]() ChemComp-UNX: ![]() ChemComp-JYR: |
由来 |
|
![]() | OXIDOREDUCTASE / respiratory enzyme / membrane protein / heme protein / apo structure / allosteric inhibitor |