1zfp
From Proteopedia
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GROWTH FACTOR RECEPTOR BINDING PROTEIN SH2 DOMAIN COMPLEXED WITH A PHOSPHOTYROSYL PENTAPEPTIDE
Contents |
Overview
An anthranyl moiety placed at the N terminus of a phosphotyrosine peptide, potentiates the inhibitory effect of this small peptide on the binding of, the Grb2 SH2 domain to the EGF receptor. Using molecular modeling, procedures based on the Lck SH2 domain structure, this observation was, rationalized in terms of a suitably favorable pi-pi stacking interaction, between the anthranyl moiety and the arginine alphaA2 (ArgalphaA2) residue, side-chain of Grb2 SH2. The crystal structure of the Grb2 SH2 domain in, complex with the inhibitor 2-Abz-EpYINQ-NH2 (IC50 26 nM) has been solved, in two different crystal forms at 2.1 and 1.8 A resolution. This structure, confirms the modeling based on the Lck SH2 domain. The ArgalphaA2 residue, is conserved in most SH2 domains. Thus, as expected, the anthranyl group, also confers high affinity to small peptide ligands of other SH2 domains, such as Lck-, PLC-gamma-amino-terminal and p85 amino-terminal SH2 domains, as demonstrated by structure affinity relationships (SAR) data. These, potent peptides with an amino-terminal surrogate group and the structure, of Grb2 SH2 domain in complex with one such peptide represent good, starting points for the design and optimization of new inhibitors of many, SH2 domains.
Disease
Known diseases associated with this structure: Central hypoventilation syndrome, congenital OMIM:[100790], Haddad syndrome OMIM:[100790]
About this Structure
1ZFP is a Single protein structure of sequence from Homo sapiens with ZN and NH2 as ligands. Full crystallographic information is available from OCA.
Reference
Structural basis for the high affinity of amino-aromatic SH2 phosphopeptide ligands., Rahuel J, Garcia-Echeverria C, Furet P, Strauss A, Caravatti G, Fretz H, Schoepfer J, Gay B, J Mol Biol. 1998 Jun 19;279(4):1013-22. PMID:9642078
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