3s8o
From Proteopedia
Crystal Structure of the Grb2 SH2 Domain in Complex with a pYXN-Derived Tripeptide
Structural highlights
FunctionGRB2_HUMAN Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway.[1] [2] [3] Isoform 2 does not bind to phosphorylated epidermal growth factor receptor (EGFR) but inhibits EGF-induced transactivation of a RAS-responsive element. Isoform 2 acts as a dominant negative protein over GRB2 and by suppressing proliferative signals, may trigger active programmed cell death.[4] [5] [6] Publication Abstract from PubMedThermodynamic parameters were determined for complex formation between the Grb2 SH2 domain and Ac-pTyr-Xaa-Asn derived tripeptides in which the Xaa residue is an alpha,alpha-cycloaliphatic amino acid that varies in ring size from three- to seven-membered. Although the six- and seven-membered ring analogs are approximately equipotent, binding affinities of those having three- to six-membered rings increase incrementally with ring size because increasingly more favorable binding enthalpies dominate increasingly less favorable binding entropies, a finding consistent with an enthalpy-driven hydrophobic effect. Crystallographic analysis reveals that the only significant differences in structures of the complexes are in the number of van der Waals contacts between the domain and the methylene groups in the Xaa residues. There is a positive correlation between buried nonpolar surface area and binding free energy and enthalpy, but not with DeltaC(p). Displacing a water molecule from a protein-ligand interface is not necessarily reflected in a favorable change in binding entropy. These findings highlight some of the fallibilities associated with commonly held views of relationships of structure and energetics in protein-ligand interactions and have significant implications for ligand design. Protein-Ligand Interactions: Thermodynamic Effects Associated with Increasing Nonpolar Surface Area.,Myslinski JM, Delorbe JE, Clements JH, Martin SF J Am Chem Soc. 2011 Oct 27. PMID:22007755[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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