2AOB

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

2AOB の概要

• エントリーDOI: 10.2210/pdb2aob/pdb
• 分子名称: 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 entities in total)
• 機能のキーワード: grb2 sh2, peptide mimetic, domain swapping, kinase signalling, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus : P62993
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 55358.52

構造登録者

Phan, J.,Shi, Z.D.,Burke, T.R.,Waugh, D.S. (登録日: 2005-08-12, 公開日: 2005-10-04, 最終更新日: 2024-02-14)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.8 Å)