6vk2

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== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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Growth factor receptor-bound protein 2 (Grb2) is an adaptor protein composed of three domains, an N-terminal SH3 (nSH3), SH2 and a C-terminal SH3 (cSH3) domains. This multi-domain protein has been reported to be a key factor in many signaling pathways related to controlling cell survival, differentiation, and growth. The Grb2-SH2 domain has been a focus for the study of the interaction with peptides and small molecules to act as inhibitors in uncontrolled cell growth, and consequently inhibit tumor proliferation. Here we describe the almost complete assignment of the free SH2 domain at pH 7. This work prepares the ground for further structural studies, backbone dynamics, mapping of interactions and drug screening and development. TalosN secondary structure prediction showed great similarity with the available structures in the PDB.
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The growth factor receptor-bound protein 2 (Grb2) is a key factor in the regulation of cell survival, proliferation, differentiation, and metabolism. In its structure, the central Src homology 2 (SH2) domain is flanked by two Src homology 3 (SH3). SH2 is the most important domain in the recognition of phosphotyrosines. Here, we present the first dynamical characterization of Grb2-SH2 domain in the free state and in the presence of phosphopeptide EpYINSQV at multiple timescales, which revealed valuable information to the understanding of phophotyrosine sensing mechanism. Grb2-SH2 presented two dynamically independent subdomains, subdomain I involved in pY recognition and subdomain II is the pY + 2 specificity pocket. Under semi-saturated concentrations of pY-pep we observed fuzzy interactions, which led to chemical exchange observed by NMR. This information was used to describe the encounter complex. The association with pY-pep is dynamic, involving fuzzy interactions and multiple conformations of pY-pep with negative and hydrophobic residues, creating an electrostatic-potential that drives the binding of pY-pep. The recognition face is wider than the binding site, with many residues beyond the central SH2 binding site participating in the association complex, which contribute to explain previously reported capability of Grb2 to recognize remote pY.
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NMR assignment of free (1)H, (15)N and (13)C-Grb2-SH2 domain.,Sanches K, Caruso IP, Almeida FCL, Melo FA Biomol NMR Assign. 2019 Oct;13(2):295-298. doi: 10.1007/s12104-019-09894-x. Epub , 2019 Apr 26. PMID:31028611<ref>PMID:31028611</ref>
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The dynamics of free and phosphopeptide-bound Grb2-SH2 reveals two dynamically independent subdomains and an encounter complex with fuzzy interactions.,Sanches K, Caruso IP, Almeida FCL, Melo FA Sci Rep. 2020 Aug 3;10(1):13040. doi: 10.1038/s41598-020-70034-w. PMID:32747626<ref>PMID:32747626</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

Revision as of 06:36, 19 August 2020

NMR solution structure of Grb2-SH2 domain at pH 7

PDB ID 6vk2

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