PDBsum entry 2a06

Oxidoreductase

PDB id: 2a06

Contents

Protein chains

443 a.a.

424 a.a.

365 a.a.

241 a.a.

196 a.a.

99 a.a.

75 a.a.

66 a.a.

42 a.a.

30 a.a.

62 a.a.

Ligands

JZR ×6

PO4 ×11

AZI ×4

UNL ×74

PEE ×5

HEM ×4

SMA ×2

_UQ ×2

CDL ×4

GOL ×7

HEC ×2

FES ×2

Waters ×1612

References listed in PDB file

Key reference

Title

Binding of the respiratory chain inhibitor antimycin to the mitochondrial bc1 complex: a new crystal structure reveals an altered intramolecular hydrogen-Bonding pattern.

Authors

L.S.Huang, D.Cobessi, E.Y.Tung, E.A.Berry.

Ref.

J Mol Biol, 2005, 351, 573-597. [DOI no: 10.1016/j.jmb.2005.05.053]

PubMed id

16024040

Abstract

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 2.28 A 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 cytochrome 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 alphaA helix.

Figure 1.
Figure 1. The structure of antimycin (stereo views). (a) From the small-molecule crystal structure42 (coordinates from the Cambridge Structure Database, CCDC # 125007). Hydrogen atoms have been removed from the carbon atoms for clarity. (b) From the structure 1PPJ, with the FSA ring and amide group in the plane of the picture. (C) As (b) but rotated 75° to view the dilactone ring nearly face-on. The electron density in (b) and (c) is a 2F[o] -F[c] map contoured at 2.1s (b) or 0.9s (c) from structure 1PPJ.

Figure 7.
Figure 7. Comparison of Q[i]-site residues and ligands in structures 1PPJ and Y21. The two structures were superimposed based on cytochrome b residues 32-51, 79-99, 113-145, 161-201, and 263-300. The backbone is shown for parts of transmembrane helices A (pink), D (red), and E (green), in color for 1PPJ and gray for Y21; as well as some of the linker region preceding helices A and D. Relevant side-chains are drawn with bonds and carbon atoms the same color as the backbone. Water molecules are shown as red spheres for 1PPJ and pink spheres for Y21. Antimycin from 1PPJ is shown as a purple ball-and stick figure with red oxygen atoms, while ubiquinone from structure Y21 is yellow. Note the relatively invariant positions of the backbone and side-chains, and the positioning of the ubiquinone ring over the amide moiety of antimycin.

The above figures are reprinted from an Open Access publication published by Elsevier: J Mol Biol (2005, 351, 573-597) copyright 2005.