title: Crystal structures of a high-affinity macrocyclic peptide mimetic in complex with the Grb2 SH2 domain.
abstract: The high-affinity binding of the growth factor receptor-bound protein 2 (Grb2) SH2 domain to tyrosine-phosphorylated cytosolic domains of receptor tyrosine kinases (RTKs) is an attractive target for therapeutic intervention in many types of cancer. We report here two crystal forms of a complex between the Grb2 SH2 domain and a potent non-phosphorus-containing macrocyclic peptide mimetic that exhibits significant anti-proliferative effects against erbB-2-dependent breast cancers. This agent represents a "second generation" inhibitor with greatly improved binding affinity and bio-availability compared to its open-chain counterpart. The structures were determined at 2.0A and 1.8A with one and two domain-swapped dimers per asymmetric unit, respectively. The mode of binding and specific interactions between the protein and the inhibitor provide insight into the high potency of this class of macrocylic compounds and may aid in further optimization as part of the iterative rational drug design process.
authors.affiliation: Macromolecular Crystallography Laboratory Center for Cancer Research, National Cancer Institute at Frederick, P.O. Box B, Frederick, MD 21702-1201, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Phan
authors.forename: Zhen-Dan
authors.initials: ZD
authors.lastname: Shi
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
authors.forename: David S
authors.initials: DS
authors.lastname: Waugh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D032701:Biomimetics; D018360:Crystallography, X-Ray; D019281:Dimerization; D051380:GRB2 Adaptor Protein; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D008024:Ligands; D010456:Peptides, Cyclic; D019000:Phosphotyrosine