Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols.
The structures of F(1)-ATPase from bovine heart mitochondria inhibited with the dietary phytopolyphenol, resveratrol, and with the related polyphenols quercetin and piceatannol have been determined at 2.3-, 2.4- and 2.7-A resolution, respectively. The inhibitors bind to a common site in the inside surface of an annulus made from loops in the three alpha- and three beta-subunits beneath the "crown" of beta-strands in their N-terminal domains. This region of F(1)-ATPase forms a bearing to allow the rotation of the tip of the gamma-subunit inside the annulus during catalysis. The binding site is a hydrophobic pocket between the C-terminal tip of the gamma-subunit and the beta(TP) subunit, and the inhibitors are bound via H-bonds mostly to their hydroxyl moieties mediated by bound water molecules and by hydrophobic interactions. There are no equivalent sites between the gamma-subunit and either the beta(DP) or the beta(E) subunit. The inhibitors probably prevent both the synthetic and hydrolytic activities of the enzyme by blocking both senses of rotation of the gamma-subunit. The beneficial effects of dietary resveratrol may derive in part by preventing mitochondrial ATP synthesis in tumor cells, thereby inducing apoptosis.
Gledhill
Jonathan R
JR
Medical Research Council Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, United Kingdom.
Montgomery
Martin G
MG
Leslie
Andrew G W
AG
Walker
John E
JE
D000818:Animals; D001665:Binding Sites; D002417:Cattle; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology*; D059808:Polyphenols; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry* / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D021122:Protein Subunits; D013267:Stilbenes; D006180:Proton-Translocating ATPases; D000077185:Resveratrol
Mol Nutr Food Res. 2005 May;49(5):405-30
15832402
Biochim Biophys Acta. 2003 Jan 20;1637(1):31-8
12527404
Circulation. 1995 Jun 1;91(11):2810-8
7758188
Cell. 2001 Aug 10;106(3):331-41
11509182
Biochim Biophys Acta. 1974 Feb 22;333(2):180-6
19400030
Curr Med Chem Anticancer Agents. 2003 Mar;3(2):77-93
12678904
Mol Cell. 2000 Oct;6(4):909-19
11090628
Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3
15299374
EMBO J. 2006 Mar 22;25(6):1396-405
16482224
Annu Rev Biochem. 1997;66:717-49
9242922
J Biol Chem. 1999 Dec 17;274(51):36261-6
10593914
Br J Pharmacol. 2000 Jul;130(5):1115-23
10882397
Blood. 1998 Aug 1;92(3):996-1002
9680369
Curr Opin Struct Biol. 2000 Dec;10(6):672-9
11114504
Biochemistry. 2004 Sep 14;43(36):11417-26
15350128
Biochem J. 2005 Mar 15;386(Pt 3):591-8
15537385
J Mol Biol. 1985 Aug 20;184(4):677-701
2864455
Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
15299926
Nat Struct Biol. 2000 Nov;7(11):1055-61
11062563
Eur J Biochem. 2004 Oct;271(19):3914-22
15373837
ACS Chem Biol. 2006 Jun 20;1(5):304-8
17163759
Life Sci. 2000 Jan 14;66(8):663-73
10680575
FEBS Lett. 1988 May 9;232(1):221-6
2896606
FEBS Lett. 2001 Apr 6;494(1-2):11-4
11297725
Nat Rev Mol Cell Biol. 2001 Sep;2(9):669-77
11533724
J Biol Chem. 2002 Jun 28;277(26):23308-13
11964400
Acta Crystallogr D Biol Crystallogr. 2004 Aug;60(Pt 8):1355-63
15272157
Nature. 2004 Jan 29;427(6973):465-8
14749837
Biochimie. 1975;57(8):959-67
130941
J Med Chem. 2004 Feb 26;47(5):1081-4
14971888
Mol Cancer Ther. 2007 Jan;6(1):163-72
17218638
Biochim Biophys Acta. 2002 Feb 15;1553(3):188-211
11997128
Science. 1999 Mar 5;283(5407):1482-8
10066162
Annu Rev Genet. 2005;39:359-407
16285865
EMBO J. 2006 Nov 15;25(22):5433-42
17082766
Biochim Biophys Acta. 2000 Mar 16;1478(1):125-37
10719181
Nat Struct Mol Biol. 2004 Feb;11(2):135-41
14730350
FEBS Lett. 1994 Feb 14;339(1-2):40-4
8313978
Proteins. 2005 Sep 1;60(4):803-6
16028220
EMBO J. 2006 Jun 21;25(12):2911-8
16791136
Biochim Biophys Acta. 2000 May 31;1458(2-3):343-55
10838049
Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9420-4
8790345
Biochem Biophys Res Commun. 1999 Aug 2;261(2):499-503
10425214
Biochem Biophys Res Commun. 1989 Nov 30;165(1):241-5
2590224
Acta Crystallogr A. 1991 Mar 1;47 ( Pt 2):110-9
2025413
Nature. 1997 Feb 13;385(6617):602-9
9024658
Mol Nutr Food Res. 2005 May;49(5):452-61
15830333
Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8646-9
16728506
Nature. 1994 Aug 25;370(6491):621-8
8065448
Acta Crystallogr D Biol Crystallogr. 2004 Aug;60(Pt 8):1441-4
15272171
Nat Struct Biol. 2000 Apr;7(4):312-21
10742177
Bioorg Med Chem Lett. 2004 Feb 23;14(4):1031-4
15013017
Genetics. 1995 Jun;140(2):435-42
7498726
J Mol Biol. 2007 Jun 8;369(3):829-40
17466326
Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):6913-7
8692918
J Biol Chem. 2007 May 11;282(19):14238-42
17350959
Curr Opin Struct Biol. 1994 Dec;4(6):912-8
7712295
Bioorg Med Chem Lett. 2004 Feb 23;14(4):1027-30
15013016
J Biol Chem. 1998 Oct 23;273(43):27873-8
9774398
Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16625-30
12486225
J Biol Chem. 1990 Mar 25;265(9):5043-8
2138624
Nat Struct Biol. 2003 Sep;10(9):744-50
12923572
Ann N Y Acad Sci. 2002 May;957:210-29
12074974
Structure. 1998 Jul 15;6(7):831-7
9687365
Biochem Biophys Res Commun. 1999 Sep 24;263(2):294-300
10491287
Biochim Biophys Acta. 2006 May-Jun;1757(5-6):286-96
16697972
Chem Biol. 2005 Apr;12(4):485-96
15850986
J Biol Chem. 1995 Sep 29;270(39):22850-4
7559418
Structure. 2002 Jan;10(1):93-103
11796114
Science. 1999 Nov 26;286(5445):1700-5
10576729
Mitochondrion. 2003 Mar;2(4):257-65
16120326
J Biol Chem. 1999 May 14;274(20):13824-9
10318787
J Biol Chem. 1995 Jun 9;270(23):14042-6
7775464
EMBO J. 2004 Jul 21;23(14):2734-44
15229653
Structure. 2000 Jun 15;8(6):567-73
10873854
Nat Struct Biol. 1999 Aug;6(8):775-84
10426957
FASEB J. 2003 Nov;17(14):1975-85
14597667
Mol Nutr Food Res. 2005 May;49(5):377-95
15830334
Chem Biol. 2004 Sep;11(9):1179-94
15380179