Crystal Structures of a High-affinity Macrocyclic Peptide Mimetic in Complex with the Grb2 SH2 Domain

Structural Basis of Binding by Cyclic Nonphosphorylated Peptide Antagonists of Grb7 Implicated in Breast Cancer Progression

“…Besides the YXN motif interactions, the positioning of an aromatic residue against the βD6 side chain (as seen for F2 in the current structure) has similarly been observed for ligands bound to the Grb2-SH2 domain. 38,39 The G7-18NATE interaction with the Grb7-SH2 domain is, however, unlike that reported for the one other ligand-bound structure of the Grb7-SH2 domain. The structure of a 10-residue phosphorylated peptide, representing the pY1339 target site of the erbB-2 receptor, bound to the Grb7-SH2 domain has been solved using NMR spectroscopy 37 (PDB IDs: 1MW4 and 2L4K).…”

Structural and energetic aspects of Grb2-SH2 domain-swapping

“…Besides the structures reported here, three other structures of ligand complexes of the domainswapped dimer of Grb2-SH2 are known (PDB codes 1FYR, 2AOA, 2AOB) [15,35]. In each of those structures the side chain of W121 adopts both open and closed conformations within the different molecules that comprise the asymmetric units.…”

Functional Implications of the Conformational Switch in AICD Peptide upon Binding to Grb2-SH2 Domain

“…Overall, the bound peptides assume a "U"-shaped structure with a type I β turn conformation. [40][41][42] The binding mode of AICD with Grb2-SH2 domain is not yet known, and considering the fact that AICD is devoid of any globular folded structure, it would be interesting to know the conformation adopted by AICD, especially the key "YENPTY" motif, upon Grb2-SH2 binding. Here, we present the high-resolution crystal structures of two AICD-derived phospho-peptides: (QNG -P YENPTY and its E → V modification QNG -P YVNPTY) in complex with the SH2 domain of Grb2 (Grb2-SH2) and complimentary spectroscopic studies to reveal their functional implications.…”