2aoa

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spinqualitylabelsall models 2aoa, resolution 1.99Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structures of a high-affinity macrocyclic peptide mimetic in complex with the Grb2 SH2 domain

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The high-affinity binding of the growth factor receptor-bound protein 2, (Grb2) SH2 domain to tyrosine-phosphorylated cytosolic domains of receptor, tyrosine kinases (RTKs) is an attractive target for therapeutic, intervention in many types of cancer. We report here two crystal forms of, a complex between the Grb2 SH2 domain and a potent, non-phosphorus-containing macrocyclic peptide mimetic that exhibits, significant anti-proliferative effects against erbB-2-dependent breast, cancers. This agent represents a "second generation" inhibitor with, greatly improved binding affinity and bio-availability compared to its, open-chain counterpart. The structures were determined at 2.0A and 1.8A, with one and two domain-swapped dimers per asymmetric unit, respectively., The mode of binding and specific interactions between the protein and the, inhibitor provide insight into the high potency of this class of, macrocylic compounds and may aid in further optimization as part of the, iterative rational drug design process.

Disease

Known diseases associated with this structure: Central hypoventilation syndrome, congenital OMIM:[100790], Haddad syndrome OMIM:[100790]

About this Structure

2AOA is a Single protein structure of sequence from Homo sapiens with S1S and P33 as ligands. Full crystallographic information is available from OCA.

Reference

Crystal structures of a high-affinity macrocyclic peptide mimetic in complex with the Grb2 SH2 domain., Phan J, Shi ZD, Burke TR Jr, Waugh DS, J Mol Biol. 2005 Oct 14;353(1):104-15. PMID:16165154

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