Searching for new allosteric sites in enzymes

被引:259
作者
Hardy, JA [1 ]
Wells, JA [1 ]
机构
[1] Sunesis Pharmaceut Inc, San Francisco, CA 94080 USA
关键词
D O I
10.1016/j.sbi.2004.10.009
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The discovery of new allosteric sites generates opportunities for the identification of novel pharmaceuticals and increases our understanding of basic biological processes. Increasingly, allosteric sites are being discovered in various families of proteins by several methods, paving the way for the development of entirely new classes of drugs with a wide range of chemotypes. New allosteric sites in enzymes have been discovered both incidentally and by directed means, and the mechanisms by which allosteric activation and inhibition occur at these sites have been investigated. By exploring recent structurally well-characterized examples, trends begin to emerge for both the modes of binding and mechanisms of inhibition.
引用
收藏
页码:706 / 715
页数:10
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共 41 条
[1]   ALLOSTERIC MODIFIERS OF HEMOGLOBIN - 2-[4-[[(3,5-DISUBSTITUTED ANILINO)CARBONYL]METHYL]PHENOXY]-2-METHYLPROPIONIC ACID-DERIVATIVES THAT LOWER THE OXYGEN-AFFINITY OF HEMOGLOBIN IN RED-CELL SUSPENSIONS, IN WHOLE-BLOOD, AND INVIVO IN RATS [J].
ABRAHAM, DJ ;
WIREKO, FC ;
RANDAD, RS ;
POYART, C ;
KISTER, J ;
BOHN, B ;
LIARD, JF ;
KUNERT, MP .
BIOCHEMISTRY, 1992, 31 (38) :9141-9149
[2]   Small-molecule inhibitors of protein-protein interactions: Progressing towards the dream [J].
Arkin, MR ;
Wells, JA .
NATURE REVIEWS DRUG DISCOVERY, 2004, 3 (04) :301-317
[3]   Multiple allosteric sites on muscarinic receptors [J].
Birdsall, NJM ;
Lazareno, S ;
Popham, A ;
Saldanha, J .
LIFE SCIENCES, 2001, 68 (22-23) :2517-2524
[4]   Peptide exosite inhibitors of factor VIIa as anticoagulants [J].
Dennis, MS ;
Eigenbrot, C ;
Skelton, NJ ;
Ultsch, MH ;
Santell, L ;
Dwyer, MA ;
O'Connell, MP ;
Lazarus, RA .
NATURE, 2000, 404 (6777) :465-470
[5]   MECHANISM OF INHIBITION OF HIV-1 REVERSE-TRANSCRIPTASE BY NONNUCLEOSIDE INHIBITORS [J].
ESNOUF, R ;
REN, JS ;
ROSS, C ;
JONES, Y ;
STAMMERS, D ;
STUART, D .
NATURE STRUCTURAL BIOLOGY, 1995, 2 (04) :303-308
[6]   Can allosteric regulation be predicted from structure? [J].
Freire, E .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (22) :11680-11682
[7]   Allosteric activators of glucokinase: Potential role in diabetes therapy [J].
Grimsby, J ;
Sarabu, R ;
Corbett, WL ;
Haynes, NE ;
Bizzarro, FT ;
Coffey, JW ;
Guertin, KR ;
Hilliard, DW ;
Kester, RF ;
Mahaney, PE ;
Marcus, L ;
Qi, LD ;
Spence, CL ;
Tengi, J ;
Magnuson, MA ;
Chu, CA ;
Dvorozniak, MT ;
Matschinsky, FM ;
Grippo, JF .
SCIENCE, 2003, 301 (5631) :370-373
[8]   Discovery of an allosteric site in the caspases [J].
Hardy, JA ;
Lam, J ;
Nguyen, JT ;
O'Brien, T ;
Wells, JA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (34) :12461-12466
[9]   Allosteric determinants in guanine nucleotide-binding proteins [J].
Hatley, ME ;
Lockless, SW ;
Gibson, SK ;
Gilman, AG ;
Ranganathan, R .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (24) :14445-14450
[10]   Allosteric inhibition through core disruption [J].
Horn, JR ;
Shoichet, BK .
JOURNAL OF MOLECULAR BIOLOGY, 2004, 336 (05) :1283-1291