6BMW
Non-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitors SHP099 and SHP504
Summary for 6BMW
| Entry DOI | 10.2210/pdb6bmw/pdb |
| Related | 6BMR 6BMU 6BMV |
| Descriptor | Tyrosine-protein phosphatase non-receptor type 11, 6-(4-azanyl-4-methyl-piperidin-1-yl)-3-[2,3-bis(chloranyl)phenyl]pyrazin-2-amine, 3-{4-[(2-chlorophenyl)methyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazolin-1-yl}-4-hydroxybenzoic acid, ... (6 entities in total) |
| Functional Keywords | shp2, ptpn11, protein tyrosine phosphatase, phosphatase, allosteric inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (Human) |
| Cellular location | Cytoplasm : Q06124 |
| Total number of polymer chains | 2 |
| Total formula weight | 122740.26 |
| Authors | |
| Primary citation | 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 Cited by 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: 29304282DOI: 10.1021/acschembio.7b00980 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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