Binding of the Respiratory Chain Inhibitor Antimycin to theMitochondrial bc1 Complex: A New Crystal Structure Reveals an AlteredIntramolecular Hydrogen-Bonding Pattern
Antimycin A (antimycin), one of the first known and most potent inhibitors of the mitochondrial respiratory chain, binds to the quinone reduction site of the cytochrome bc1 complex.Structure-activity-relationship studies have shown that the N-formylamino-salicyl-amide group is responsible for most of the binding specificity, and suggested that a low pKa for the phenolic OH group and an intramolecular H-bond between that OH and the carbonyl O of the salicylamide linkage are important. Two previous X-ray structures of antimycin bound to vertebrate bc1 complex gave conflicting results. A new structure reported here of the bovine mitochondrial bc1 complex at 2.28Angstrom resolution with antimycin bound, allows us for the first time to reliably describe the binding of antimycin and shows that the intramolecular hydrogen bond described in solution and in the small-molecule structure is replaced by one involving the NH rather than carbonyl O of the amide linkage, with rotation of the amide group relative to the aromatic ring. The phenolic OH and formylamino N form H-bonds with conserved Asp228 of cyt b, and the formylamino O H-bonds via a water molecule to Lys227. A strong density the right size and shape for a diatomic molecule is found between the other side of the dilactone ring and the alpha-A helix.
- Research Organization:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Organization:
- USDOE Director. Office of Science. Office of Biological andEnvironmental Research; National Institutes of Health Grants DK44842 andGM62563
- DOE Contract Number:
- DE-AC02-05CH11231
- OSTI ID:
- 862176
- Report Number(s):
- LBNL-58036; JMOBAK; R&D Project: 864U1E; BnR: 400412000; TRN: US200602%%84
- Journal Information:
- Journal of Molecular Biology, Vol. 531, Issue 3; Related Information: Journal Publication Date: 08/19/2005; ISSN 0022-2836
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
36 MATERIALS SCIENCE
59 BASIC BIOLOGICAL SCIENCES
AMIDES
ANTIBIOTICS
AROMATICS
BENZOQUINONES
CARBONYLS
CATTLE
CRYSTAL STRUCTURE
CYTOCHROMES
HYDROGEN
RESOLUTION
ROTATION
SHAPE
SPECIFICITY
VERTEBRATES
WATER
cytochrome bc1 antimycin respiratory chain membrane proteincomplex inhibitor binding site