Modeling the G-protein-coupled neuropeptide Y Y1 receptor agonist and antagonist binding sites

被引：48

作者：

Du, P ^{[1
]}

Salon, JA ^{[1
]}

Tamm, JA ^{[1
]}

Hou, CF ^{[1
]}

Cui, WL ^{[1
]}

Walker, MW ^{[1
]}

Adham, N ^{[1
]}

Dhanoa, DS ^{[1
]}

Islam, I ^{[1
]}

Vaysse, PJJ ^{[1
]}

Dowling, B ^{[1
]}

Shifman, Y ^{[1
]}

Boyle, N ^{[1
]}

Rueger, H ^{[1
]}

Schmidlin, T ^{[1
]}

Yamaguchi, Y ^{[1
]}

Branchek, TA ^{[1
]}

Weinshank, RL ^{[1
]}

Gluchowski, C ^{[1
]}

机构：

[1] CIBA GEIGY LTD,CH-4002 BASEL,SWITZERLAND

来源：

PROTEIN ENGINEERING | 1997年 / 10卷 / 02期

关键词：

agonist; antagonist; model; mutagenesis; neuropeptide;

D O I：

10.1093/protein/10.2.109

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：

Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor (GPCR) superfamily and mediate several physiological responses, such as blood pressure, food intake, sedation and memory retention. To understand the interactions between the NPY Y1 receptor subtype and its ligands, computer modeling was applied to the natural peptide agonist, NPY and a small molecule antagonist, BIBP3226. An agonist and antagonist binding domain was elucidated using mutagenesis data for the Y1 receptor as well as for other GPCR families. The agonist and antagonist ligands which were investigated appear to share common residues for their interaction within the transmembrane regions of the Y1 receptor structure, including Gln120, Asn283 and His306. This is in contrast to findings with tachykinin receptors where the binding domains of the non-peptide antagonists have very little in common with the binding domains of the agonist, substance-P. In addition, a hydrogen bond between the hydroxyl group of Tyr36 of NPY and the side chain of Gln219, an interaction that is absent in the model complex between Y1 and the antagonist BIBP3226, is proposed as one of the potential interactions necessary for receptor activation.

引用

页码：109 / 117

页数：9

共 57 条

[11] DONNELLY D, 1994, RECEPTOR CHANNEL, V2, P61
[12] SEQUENCE DIVERGENCE ANALYSIS FOR THE PREDICTION OF 7-HELIX MEMBRANE-PROTEIN STRUCTURES .1. COMPARISON WITH BACTERIORHODOPSIN
DU, P
ALKORTA, I
[J]. PROTEIN ENGINEERING, 1994, 7 (10): : 1221 - 1229
[13] MAPPING THE LIGAND-BINDING SITE OF THE NK-1 RECEPTOR
FONG, TM
HUANG, RRC
YU, H
STRADER, CD
[J]. REGULATORY PEPTIDES, 1993, 46 (1-2) : 43 - 48
[14] Gehlert DR, 1996, MOL PHARMACOL, V49, P224
[15] EXPRESSION CLONING AND PHARMACOLOGICAL CHARACTERIZATION OF A HUMAN HIPPOCAMPAL NEUROPEPTIDE-Y PEPTIDE YY Y2 RECEPTOR SUBTYPE
GERALD, C
WALKER, MW
VAYSSE, PJJ
HE, CG
BRANCHEK, TA
WEINSHANK, RL
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (45) : 26758 - 26761
[16] TACHYKININ NONPEPTIDE ANTAGONISTS - BINDING DOMAIN AND MOLECULAR-MODE OF ACTION
GETHER, U
LOWE, JA
SCHWARTZ, TW
[J]. BIOCHEMICAL SOCIETY TRANSACTIONS, 1995, 23 (01) : 96 - 102
[17] AUTOMATED DOCKING OF SUBSTRATES TO PROTEINS BY SIMULATED ANNEALING
GOODSELL, DS
OLSON, AJ
[J]. PROTEINS-STRUCTURE FUNCTION AND GENETICS, 1990, 8 (03): : 195 - 202
[18] A MODEL FOR THE C5A RECEPTOR AND FORT ITS INTERACTION WITH THE LIGAND
GROTZINGER, J
ENGELS, M
JACOBY, E
WOLLMER, A
STRASSBURGER, W
[J]. PROTEIN ENGINEERING, 1991, 4 (07): : 767 - 771
[19] NEUROPEPTIDE-Y EFFECTOR SYSTEMS - PERSPECTIVES FOR DRUG DEVELOPMENT
GRUNDEMAR, L
HAKANSON, R
[J]. TRENDS IN PHARMACOLOGICAL SCIENCES, 1994, 15 (05) : 153 - 159
[20] Grundemar L., 1993, BIOL NEUROPEPTIDE RE, P197, DOI [10.1007/978-1-59259-465-8_5, DOI 10.1007/978-1-59259-465-8_5]

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