1BM2

GRB2-SH2 DOMAIN IN COMPLEX WITH CYCLO-[N-ALPHA-ACETYL-L-THI ALYSYL-O-PHOSPHOTYROSYL-VALYL-ASPARAGYL-VALYL-PROLYL] (PKF273-791)

Summary for 1BM2

• Entry DOI: 10.2210/pdb1bm2/pdb
• Descriptor: PROTEIN (GROWTH FACTOR RECEPTOR BOUND PROTEIN 2), PROTEIN (PKF273-791) (3 entities in total)
• Functional Keywords: sh2 domain, signal transduction, adaptor protein, ras pathway, cyclic peptide, hormone-growth factor complex, hormone/growth factor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 14420.26

Authors

Rondeau, J.M.,Zurini, M. (deposition date: 1998-07-27, release date: 1998-08-05, Last modification date: 2024-11-13)

Primary citation

Ettmayer, P.,France, D.,Gounarides, J.,Jarosinski, M.,Martin, M.S.,Rondeau, J.M.,Sabio, M.,Topiol, S.,Weidmann, B.,Zurini, M.,Bair, K.W.
Structural and conformational requirements for high-affinity binding to the SH2 domain of Grb2(1).
J.Med.Chem., 42:971-980, 1999

PubMed Abstract: Following earlier work on cystine-bridged peptides, cyclic phosphopeptides containing nonreducible mimics of cystine were synthesized that show high affinity and specificity toward the Src homology (SH2) domain of the growth factor receptor-binding protein (Grb2). Replacement of the cystine in the cyclic heptapeptide cyclo(CYVNVPC) by D-alpha-acetylthialysine or D-alpha-lysine gave cyclo(YVNVP(D-alpha-acetyl-thiaK)) (22) and cyclo(YVNVP(D-alpha-acetyl-K)) (30), which showed improved binding 10-fold relative to that of the control peptide KPFYVNVEF (1). NMR spectroscopy and molecular modeling experiments indicate that a beta-turn conformation centered around YVNV is essential for high-affinity binding. X-ray structure analyses show that the linear peptide 1 and the cyclic compound 21 adopt a similar binding mode with a beta-turn conformation. Our data confirm the unique structural requirements of the ligand binding site of the SH2 domain of Grb2. Moreover, the potency of our cyclic lactams can be explained by the stabilization of the beta-turn conformation by three intramolecular hydrogen bonds (one mediated by an H2O molecule). These stable and easily accessible cyclic peptides can serve as templates for the evaluation of phosphotyrosine surrogates and further chemical elaboration.

PubMed: 10090780
DOI: 10.1021/jm9811007

Experimental method

X-RAY DIFFRACTION (2.1 Å)