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Structure paper

TitleIdentifying antibiotics based on structural differences in the conserved allostery from mitochondrial heme-copper oxidases.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 7591, Year 2022
Publish dateDec 8, 2022
AuthorsYuya 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 AbstractAntimicrobial 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.
External linksNat Commun / PubMed:36481732 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.2 - 3.09 Å
Structure data

33293

7xmc

EMDB-33293, PDB-7xmc:
Cryo-EM structure of Cytochrome bo3 from Escherichia coli, apo structure with DMSO
Method: EM (single particle) / Resolution: 3.09 Å

33294

7xmd

EMDB-33294, PDB-7xmd:
Cryo-EM structure of Cytochrome bo3 from Escherichia coli, the structure complexed with an allosteric inhibitor N4
Method: EM (single particle) / Resolution: 2.99 Å

PDB-7xma:
Crystal structure of Bovine heart cytochrome c oxidase, apo structure with DMSO
Method: X-RAY DIFFRACTION / Resolution: 2.2 Å

PDB-7xmb:
Crystal structure of Bovine heart cytochrome c oxidase, the structure complexed with an allosteric inhibitor T113
Method: X-RAY DIFFRACTION / Resolution: 2.2 Å

Chemicals

ChemComp-HEA:
HEME-A

ChemComp-CU:
COPPER (II) ION

ChemComp-MG:
Unknown entry

ChemComp-NA:
Unknown entry

ChemComp-PER:
PEROXIDE ION

ChemComp-PGV:
(1R)-2-{[{[(2S)-2,3-DIHYDROXYPROPYL]OXY}(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL (11E)-OCTADEC-11-ENOATE / phospholipid*YM

ChemComp-TGL:
TRISTEAROYLGLYCEROL

ChemComp-CUA:
DINUCLEAR COPPER ION

ChemComp-CDL:
CARDIOLIPIN / phospholipid*YM

ChemComp-CHD:
CHOLIC ACID

ChemComp-PEK:
(1S)-2-{[(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(STEAROYLOXY)METHYL]ETHYL (5E,8E,11E,14E)-ICOSA-5,8,11,14-TETRAENOATE / phospholipid*YM

ChemComp-PSC:
(7R,17E,20E)-4-HYDROXY-N,N,N-TRIMETHYL-9-OXO-7-[(PALMITOYLOXY)METHYL]-3,5,8-TRIOXA-4-PHOSPHAHEXACOSA-17,20-DIEN-1-AMINIUM 4-OXIDE / phospholipid*YM

ChemComp-ZN:
Unknown entry

ChemComp-DMU:
DECYL-BETA-D-MALTOPYRANOSIDE / detergent*YM

ChemComp-HOH:
WATER

ChemComp-J6X:
2-(4-methyl-1,3-thiazol-2-yl)-1-benzothiophen-3-ol

ChemComp-HEO:
HEME O

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE

ChemComp-PEE:
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE, phospholipid*YM

ChemComp-UNX:
Unknown entry

ChemComp-JYR:
methyl 3-oxidanyl-5-[oxidanyl(oxidanylidene)-$l^{4}-azanyl]-1-benzothiophene-2-carboxylate

Source
  • escherichia coli (E. coli)
  • bos taurus (cattle)
KeywordsOXIDOREDUCTASE / respiratory enzyme / membrane protein / heme protein / apo structure / allosteric inhibitor

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