2h5k
Crystal Structure of Complex Between the Domain-Swapped Dimeric Grb2 SH2 Domain and Shc-Derived Ligand, Ac-NH-pTyr-Val-Asn-NH2
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OverviewOverview
The SH2 domain of growth factor receptor-bound protein 2 (Grb2) has been, the focus of numerous studies, primarily because of the important roles it, plays in signal transduction. More recently, it has emerged as a useful, protein to study the consequences of ligand preorganization upon, energetics and structure in protein-ligand interactions. The Grb2-SH2, domain is known to form a domain-swapped dimer, and as part of our, investigations toward correlating structure and energetics in biological, systems, we examined the effects that domain-swapping dimerization of the, Grb2-SH2 domain had upon ligand binding affinities. Isothermal titration, calorimetry was performed using Grb2-SH2 in both its monomeric and, domain-swapped dimeric forms and a phosphorylated tripeptide, AcNH-pTyr-Val-Asn-NH(2) that is similar to the Shc sequence recognized by, Grb2-SH2 in vivo. The two binding sites of domain-swapped dimer exhibited, a 4- and a 13-fold reduction in ligand affinity compared to monomer., Crystal structures of peptide-bound and uncomplexed forms of Grb2-SH2, domain-swapped dimer were obtained and reveal that the orientation of, residues V122, V123, and R142 may influence the conformation of W121, an, amino acid that is believed to play an important role in Grb2-SH2 ligand, sequence specificity. These findings suggest that domain-swapping of, Grb2-SH2 not only results in a lower affinity for a Shc-derived ligand, but it may also affect ligand specificity.
DiseaseDisease
Known diseases associated with this structure: Central hypoventilation syndrome, congenital OMIM:[100790], Haddad syndrome OMIM:[100790]
About this StructureAbout this Structure
2H5K is a Single protein structure of sequence from Homo sapiens with CAC, ACE and NH2 as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Structural and energetic aspects of Grb2-SH2 domain-swapping., Benfield AP, Whiddon BB, Clements JH, Martin SF, Arch Biochem Biophys. 2007 Jun 1;462(1):47-53. Epub 2007 Apr 2. PMID:17466257
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