PDBsum entry 2jyq

Transferase

PDB id: 2jyq

Contents

Protein chain

106 a.a. *

* Residue conservation analysis

PDB id:

2jyq

Name:

Transferase

Title:

Nmr structure of the apo v-src sh2 domain

Structure:

Tyrosine-protein kinase transforming protein src. Chain: a. Fragment: sh2 domain. Synonym: p60-src, v-src, pp60v-src. Engineered: yes

Source:

Rous sarcoma virus. Organism_taxid: 11886. Strain: schmidt-ruppin e. Gene: v-src. Expressed in: escherichia coli. Expression_system_taxid: 562.

NMR struc:

20 models

Authors:

J.D.Taylor,A.Ababou,M.A.Williams,J.E.Ladbury

Key ref:

J.D.Taylor et al. (2008). Structure, dynamics, and binding thermodynamics of the v-Src SH2 domain: implications for drug design. Proteins, 73, 929-940. PubMed id: 18536014

Date:

17-Dec-07 Release date: 24-Jun-08

Protein chain

P63185  (SRC_RSVSE) -  Tyrosine-protein kinase transforming protein Src from Rous sarcoma virus subgroup E (strain Schmidt-Ruppin)

Seq: 526 a.a.

Struc: 106 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

Proteins 73:929-940 (2008)

PubMed id: 18536014

Structure, dynamics, and binding thermodynamics of the v-Src SH2 domain: implications for drug design.

J.D.Taylor, A.Ababou, R.R.Fawaz, C.J.Hobbs, M.A.Williams, J.E.Ladbury.

ABSTRACT

SH2 domains provide fundamental recognition sites in tyrosine kinase-mediated signaling pathways which, when aberrant, give rise to disease states such as cancer, diabetes, and immune deficiency. Designing specific inhibitors that target the SH2 domain-binding site, however, have presented a major challenge. Despite well over a decade of intensive research, clinically useful SH2 domain inhibitors have yet to become available. A better understanding of the structural, dynamic, and thermodynamic contributions to ligand binding of individual SH2 domains will provide some insight as to whether inhibitor development is possible. We report the first high resolution solution structure of the apo-v-Src SH2 domain. This is accompanied by the analysis of backbone dynamics and pK(a) values within the apo- and peptide-bound states. Our results indicate that the phosphotyrosine (pY) pocket is tightly structured and hence not adaptable to exogenous ligands. On the other hand, the pocket which accommodates residues proximal and C-terminal of the pY (pY + 3) or so-called specificity determining region, is a large dynamic-binding surface. This appears to allow a high level of promiscuity in binding. Binding of a series of synthetic, phosphotyrosyl, peptidomimetic compounds designed to explore interactions in the pY + 3 pocket further demonstrates the ability of the SH2 domain to accommodate diverse ligands. The thermodynamic parameters of these interactions show dramatic enthalpy/entropy compensation. These data suggest that the v-Src SH2 domain does not have a highly specific secondary-binding site, which clearly presents a major hurdle to design selective inhibitors.