2AOA

Crystal structures of a high-affinity macrocyclic peptide mimetic in complex with the Grb2 SH2 domain

Summary for 2AOA

• Entry DOI: 10.2210/pdb2aoa/pdb
• Descriptor: Growth factor receptor-bound protein 2, 2-(4-((9S,10S,14S,Z)-18-(2-AMINO-2-OXOETHYL)-9-(CARBOXYMETHYL)-14-(NAPHTHALEN-1-YLMETHYL)-8,17,20-TRIOXO-7,16,19-TRIAZASPIRO[5.14]ICOS-11-EN-10-YL)PHENYL)MALONIC ACID, 3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL, ... (4 entities in total)
• Functional Keywords: grb2 sh2, domain-swapped, peptide mimetic, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : P62993
• Total number of polymer chains: 2
• Total formula weight: 25741.17

Authors

Phan, J.,Shi, Z.D.,Burke, T.R.,Waugh, D.S. (deposition date: 2005-08-12, release date: 2005-10-04, Last modification date: 2024-02-14)

Primary citation

Phan, J.,Shi, Z.D.,Burke, T.R.,Waugh, D.S.
Crystal Structures of a High-affinity Macrocyclic Peptide Mimetic in Complex with the Grb2 SH2 Domain.
J.Mol.Biol., 353:104-115, 2005

PubMed 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.

PubMed: 16165154
DOI: 10.1016/j.jmb.2005.08.037

Experimental method

X-RAY DIFFRACTION (1.99 Å)