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Titolo:
Two crystal structures of human neutrophil collagenase, one complexed witha primed- and the other with an unprimed-side inhibitor: Implications for drug design
Autore:
Gavuzzo, E; Pochetti, G; Mazza, F; Gallina, C; Gorini, B; DAlessio, S; Pieper, M; Tschesche, H; Tucker, PA;
Indirizzi:
CNR, Ist Strutturist Chim, I-00016 Monterotondo, Italy CNR Monterotondo Italy I-00016 tturist Chim, I-00016 Monterotondo, Italy Univ Aquila, Dipartimento Chim Ingn Chim & Mat, I-67010 Coppito, Italy Univ Aquila Coppito Italy I-67010 ngn Chim & Mat, I-67010 Coppito, Italy Univ G DAnnunzio, Dipartimento Sci Farmaco, I-66100 Chieti, Italy Univ G DAnnunzio Chieti Italy I-66100 Sci Farmaco, I-66100 Chieti, Italy Univ La Sapienza, CNR, Ctr Studio Chim Farmaco, I-00185 Rome, Italy Univ La Sapienza Rome Italy I-00185 io Chim Farmaco, I-00185 Rome, Italy Polifarma Res Ctr, I-00185 Rome, Italy Polifarma Res Ctr Rome Italy I-00185 ifarma Res Ctr, I-00185 Rome, Italy Univ Bielefeld, Fak Chem, Abt Biochem 1, D-33615 Bielefeld, Germany Univ Bielefeld Bielefeld Germany D-33615 m 1, D-33615 Bielefeld, Germany DESY, EMBL, D-22603 Hamburg, Germany DESY Hamburg Germany D-22603DESY, EMBL, D-22603 Hamburg, Germany
Titolo Testata:
JOURNAL OF MEDICINAL CHEMISTRY
fascicolo: 18, volume: 43, anno: 2000,
pagine: 3377 - 3385
SICI:
0022-2623(20000907)43:18<3377:TCSOHN>2.0.ZU;2-N
Fonte:
ISI
Lingua:
ENG
Soggetto:
MATRIX METALLOPROTEINASE INHIBITORS; X-RAY STRUCTURE; CATALYTIC DOMAIN; ADAMALYSIN-II; SULFONAMIDE JUNCTION; SEQUENCE SPECIFICITIES; MOLECULAR RECOGNITION; SUBSTRATE-SPECIFICITY; POTENT INHIBITORS; IV COLLAGENASES;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
60
Recensione:
Indirizzi per estratti:
Indirizzo: Mazza, F CNR, Ist Strutturist Chim, CP 10, I-00016 Monterotondo, Italy CNRCP 10 Monterotondo Italy I-00016 I-00016 Monterotondo, Italy
Citazione:
E. Gavuzzo et al., "Two crystal structures of human neutrophil collagenase, one complexed witha primed- and the other with an unprimed-side inhibitor: Implications for drug design", J MED CHEM, 43(18), 2000, pp. 3377-3385

Abstract

Two crystal structures of human neutrophil collagenase (HNC, MMP-8), one complexed with a primed- and the other with an unprimed-side inhibitor, weredetermined using synchrotron radiation at 100 K. Both inhibitors contain non-hydroxamate zinc-binding functions. The Pro-Leu-L-Trp(P)(OH)(2) occupiesthe unprimed region of the active site, furnishes new structural information regarding interaction between the catalytic zinc ion and the phosphonategroup, and is the only example of occupation of the S-1 subsite of MMP-8 by the bulky tryptophan side chain. The (R)-2-(biphenyl-4-ylsulfonyl)-1,2,3,4-tetrahydroisochinolin-3-carboxylic acid, a conformationally constrained D-Tic derivative, accommodates its biphenyl substituent into the deep primary specificity S-1' subsite, inducing a widening of the entrance to this pocket; this modification of the protein, mainly consisting in a shift of the segment centered at Pro217, is observed for the first time in MMP-8 complexes. Cation-aromatic interactions can stabilize the formation of both complexes, and the beneficial effect of aromatic substituents in proximity of thecatalytic zinc ion is discussed. The phosphonate group bound to either a primed- or unprimed-side inhibitor maintains the same relative position withrespect to the catalytic zinc ion, suggesting that this binding function can be exploited for the design of combined inhibitors assembled to interactwith both primed and unprimed regions of the active cleft.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 27/09/20 alle ore 21:56:29