PDBsum entry 1bhh

Sh2 domain

PDB id: 1bhh

Contents

Protein chain

104 a.a. *

Waters ×141

* Residue conservation analysis

PDB id:

1bhh

Name:

Sh2 domain

Title:

Free p56lck sh2 domain

Structure:

T-lymphocyte-specific protein tyrosine kinase p56lck. Chain: a. Fragment: sh2 domain. Engineered: yes. P56 lck tyrosine kinase sh2 domain. Chain: b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562

Biol. unit:

Tetramer (from PQS)

Resolution:

1.90Å R-factor: 0.240

Authors:

L.Tong,T.C.Warren,S.Lukas,J.Schembri-King,R.Betageri,J.R.Proudfoot, S.Jakes

Key ref:

L.Tong et al. (1998). Carboxymethyl-phenylalanine as a replacement for phosphotyrosine in SH2 domain binding. J Biol Chem, 273, 20238-20242. PubMed id: 9685372 DOI: 10.1074/jbc.273.32.20238

Date:

08-Jun-98 Release date: 21-Oct-98

Protein chains

P06239  (LCK_HUMAN) -  Tyrosine-protein kinase Lck from Homo sapiens

Seq: 509 a.a.

Struc: 104 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1074/jbc.273.32.20238

J Biol Chem 273:20238-20242 (1998)

PubMed id: 9685372

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

L.Tong, T.C.Warren, S.Lukas, J.Schembri-King, R.Betageri, J.R.Proudfoot, S.Jakes.

ABSTRACT

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 A 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 A 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.

Selected figure(s)

Figure 1.
Fig. 1. The chemical structure of the p56^lck SH2 domain inhibitor used in the current study. The inhibitor contains a cmF residue as a replacement for the pY residue. The cmFEEI inhibitor is about 450-fold less potent than the pYEEI inhibitor (pH 7.4) in the binding of the SH2 domain.

Figure 2.
Fig. 2. A, comparison of the overall bound conformations of the cmFEEI inhibitor (in cyan for carbon atoms) and the pYEEI inhibitor (in white for carbon atoms). The oxygen atoms are shown in red, nitrogen is in blue, and phosphorus is in yellow. Note the remarkable similarity for the Ile residue at the pY+3 position. B, close-up of the conformational overlap of the cmF and the Tyr(P) residues, showing the translation of the phenyl ring in the cmF inhibitor. The oxygen atoms on the phosphate group are numbered. C, same as B, viewed 90 ° away around the horizontal axis, showing the rotation of the phenyl ring in the cmF inhibitor.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (1998, 273, 20238-20242) copyright 1998.

Figures were selected by an automated process.