7XMD
Cryo-EM structure of Cytochrome bo3 from Escherichia coli, the structure complexed with an allosteric inhibitor N4
Summary for 7XMD
Entry DOI | 10.2210/pdb7xmd/pdb |
EMDB information | 33294 |
Descriptor | Cytochrome bo(3) ubiquinol oxidase subunit 1, UNKNOWN ATOM OR ION, Ubiquinol oxidase subunit 2, ... (10 entities in total) |
Functional Keywords | respiratory enzyme, membrane protein, heme protein, allosteric inhibitor, oxidoreductase |
Biological source | Escherichia coli More |
Total number of polymer chains | 4 |
Total formula weight | 148574.18 |
Authors | Nishida, Y.,Shigematsu, H.,Iwamoto, T.,Takashima, S.,Shintani, Y. (deposition date: 2022-04-25, release date: 2022-12-21, Last modification date: 2024-07-03) |
Primary citation | Nishida, Y.,Yanagisawa, S.,Morita, R.,Shigematsu, H.,Shinzawa-Itoh, K.,Yuki, H.,Ogasawara, S.,Shimuta, K.,Iwamoto, T.,Nakabayashi, C.,Matsumura, W.,Kato, H.,Gopalasingam, C.,Nagao, T.,Qaqorh, T.,Takahashi, Y.,Yamazaki, S.,Kamiya, K.,Harada, R.,Mizuno, N.,Takahashi, H.,Akeda, Y.,Ohnishi, M.,Ishii, Y.,Kumasaka, T.,Murata, T.,Muramoto, K.,Tosha, T.,Shiro, Y.,Honma, T.,Shigeta, Y.,Kubo, M.,Takashima, S.,Shintani, Y. Identifying antibiotics based on structural differences in the conserved allostery from mitochondrial heme-copper oxidases. Nat Commun, 13:7591-7591, 2022 Cited by PubMed Abstract: 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. PubMed: 36481732DOI: 10.1038/s41467-022-34771-y PDB entries with the same primary citation |
Experimental method | ELECTRON MICROSCOPY (2.99 Å) |
Structure validation
Download full validation report