Carboxymethyl-phenylalanine as a replacement for phosphotyrosine in SH2 domain binding

被引：45

作者：

Tong, L ^{[1
]}

Warren, TC ^{[1
]}

Lukas, S ^{[1
]}

Schembri-King, J ^{[1
]}

Betageri, R ^{[1
]}

Proudfoot, JR ^{[1
]}

Jakes, S ^{[1
]}

机构：

[1] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 1998年 / 273卷 / 32期

关键词：

D O I：

10.1074/jbc.273.32.20238

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 crystal structure of human p56(lck) SH2 domain in complex with an inhibitor containing the singly charged p-(carboxymethyl)phenylalanine residue (cmF) as a phosphotyrosine (Tyr(P) or pY) replacement has been determined at 1.8 Angstrom resolution. The binding mode of the acetyl-cmF-Glu-Glu-Ile (cmFEEI) inhibitor is very similar to that of the pYEEI inhibitor, confirming that the cmFEEI inhibitor has a similar mechanism of SH2 domain inhibition despite its significantly reduced potency. Observed conformational differences in the side chain of the cmF residue can be interpreted in terms of maintaining similar interactions with the SH2 domain as the Tyr(P) residue. The crystal structure of the free p56(lck) SH2 domain has been determined at 1.9 Angstrom resolution and shows an open conformation for the BC loop and an open phosphotyrosine binding pocket, in contrast to earlier studies on the src SH2 domain that showed mostly closed conformation. The structural information presented here suggests that the carboxymethyl-phenylalanine residue may be a viable Tyr(P) replacement and represents an attractive starting point for the design and development of SH2 domain inhibitors with better pharmaceutical profiles.

引用

页码：20238 / 20242

页数：5

共 22 条

[11] Nonphosphorylated peptide ligands for the Grb2 Src homology 2 domain [J].

Oligino, L ;

Lung, FDT ;

Sastry, L ;

Bigelow, J ;

Cao, T ;

Curran, M ;

Burke, TR ;

Wang, SM ;

Krag, D ;

Roller, PP ;

King, CR .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (46) :29046-29052

[12]

OTWINOWSKI Z, 1993, DATA COLLECTION PROC, P56

[13] SH2 AND SH3 DOMAINS [J].

PAWSON, T ;

SCHLESSINGER, J .

CURRENT BIOLOGY, 1993, 3 (07) :434-442

[14] Design, synthesis, and cocrystal structure of a nonpeptide Src SH2 domain ligand [J].

Plummer, MS ;

Holland, DR ;

Shahripour, A ;

Lunney, EA ;

Fergus, JH ;

Marks, JS ;

McConnell, P ;

Mueller, WT ;

Sawyer, TK .

JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (23) :3719-3725

[15] Novel phosphotyrosine mimetics in the design of peptide ligands for pp60(src) SH2 domain [J].

Shahripour, A ;

Plummer, MS ;

Lunney, EA ;

Para, KS ;

Stankovic, CJ ;

Rubin, JR ;

Humblet, C ;

Fergus, JH ;

Marks, JS ;

Herrera, R ;

Hubbell, SE ;

Saltiel, AR ;

Sawyer, TK .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1996, 6 (11) :1209-1214

[16] CARBOXYLIC-ACIDS AND TETRAZOLES AS ISOSTERIC REPLACEMENTS FOR SULFATE IN CHOLECYSTOKININ ANALOGS [J].

TILLEY, JW ;

DANHO, W ;

LOVEY, K ;

WAGNER, R ;

SWISTOK, J ;

MAKOFSKE, R ;

MICHALEWSKY, J ;

TRISCARI, J ;

NELSON, D ;

WEATHERFORD, S .

JOURNAL OF MEDICINAL CHEMISTRY, 1991, 34 (03) :1125-1136

[17] REPLACE, A SUITE OF COMPUTER-PROGRAMS FOR MOLECULAR-REPLACEMENT CALCULATIONS [J].

TONG, L .

JOURNAL OF APPLIED CRYSTALLOGRAPHY, 1993, 26 :748-751

[18] Combined molecular replacement [J].

Tong, L .

ACTA CRYSTALLOGRAPHICA SECTION A, 1996, 52 :782-784

[19] Crystal structures of the human p56(lck) SH2 domain in complex with two short phosphotyrosyl peptides at 1.0 angstrom and 1.8 angstrom resolution [J].

Tong, L ;

Warren, TC ;

King, J ;

Betageri, R ;

Rose, J ;

Jakes, S .

JOURNAL OF MOLECULAR BIOLOGY, 1996, 256 (03) :601-610

[20] BINDING OF A HIGH-AFFINITY PHOSPHOTYROSYL PEPTIDE TO THE SRC SH2 DOMAIN - CRYSTAL-STRUCTURES OF THE COMPLEXED AND PEPTIDE-FREE FORMS [J].

WAKSMAN, G ;

SHOELSON, SE ;

PANT, N ;

COWBURN, D ;

KURIYAN, J .

CELL, 1993, 72 (05) :779-790

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