6BMX

Non-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitor SHP844

6BMX の概要

• エントリーDOI: 10.2210/pdb6bmx/pdb
• 関連するPDBエントリー: 6BMR 6BMU 6BMV 6BMW
• 分子名称: Tyrosine-protein phosphatase non-receptor type 11, 1-(3-chloro-4-{[1-(2-hydroxy-3-methoxyphenyl)-5-oxo[1,2,4]triazolo[4,3-a]quinazolin-4(5H)-yl]methyl}benzene-1-carbonyl)-L-proline, PHOSPHATE ION, ... (5 entities in total)
• 機能のキーワード: shp2, ptpn11, protein tyrosine phosphatase, phosphatase, allosteric inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : Q06124
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 122290.02

構造登録者

Stams, T.,Fodor, M. (登録日: 2017-11-15, 公開日: 2018-01-17, 最終更新日: 2023-10-04)

主引用文献

Fodor, M.,Price, E.,Wang, P.,Lu, H.,Argintaru, A.,Chen, Z.,Glick, M.,Hao, H.X.,Kato, M.,Koenig, R.,LaRochelle, J.R.,Liu, G.,McNeill, E.,Majumdar, D.,Nishiguchi, G.A.,Perez, L.B.,Paris, G.,Quinn, C.M.,Ramsey, T.,Sendzik, M.,Shultz, M.D.,Williams, S.L.,Stams, T.,Blacklow, S.C.,Acker, M.G.,LaMarche, M.J.
Dual Allosteric Inhibition of SHP2 Phosphatase.
ACS Chem. Biol., 13:647-656, 2018

PubMed Abstract: SHP2 is a cytoplasmic protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell proliferation, differentiation, and survival. Recently, we reported an allosteric mechanism of inhibition that stabilizes the auto-inhibited conformation of SHP2. SHP099 (1) was identified and characterized as a moderately potent, orally bioavailable, allosteric small molecule inhibitor, which binds to a tunnel-like pocket formed by the confluence of three domains of SHP2. In this report, we describe further screening strategies that enabled the identification of a second, distinct small molecule allosteric site. SHP244 (2) was identified as a weak inhibitor of SHP2 with modest thermal stabilization of the enzyme. X-ray crystallography revealed that 2 binds and stabilizes the inactive, closed conformation of SHP2, at a distinct, previously unexplored binding site-a cleft formed at the interface of the N-terminal SH2 and PTP domains. Derivatization of 2 using structure-based design resulted in an increase in SHP2 thermal stabilization, biochemical inhibition, and subsequent MAPK pathway modulation. Downregulation of DUSP6 mRNA, a downstream MAPK pathway marker, was observed in KYSE-520 cancer cells. Remarkably, simultaneous occupation of both allosteric sites by 1 and 2 was possible, as characterized by cooperative biochemical inhibition experiments and X-ray crystallography. Combining an allosteric site 1 inhibitor with an allosteric site 2 inhibitor led to enhanced pharmacological pathway inhibition in cells. This work illustrates a rare example of dual allosteric targeted protein inhibition, demonstrates screening methodology and tactics to identify allosteric inhibitors, and enables further interrogation of SHP2 in cancer and related pathologies.

PubMed: 29304282
DOI: 10.1021/acschembio.7b00980

実験手法

X-RAY DIFFRACTION (2.424 Å)