4RDD
Co-crystal structure of SHP2 in complex with a Cefsulodin derivative
Summary for 4RDD
| Entry DOI | 10.2210/pdb4rdd/pdb |
| Descriptor | Tyrosine-protein phosphatase non-receptor type 11, 1-({(2R)-4-carboxy-2-[(R)-carboxy{[(2R)-2-phenyl-2-sulfoacetyl]amino}methyl]-3,6-dihydro-2H-1,3-thiazin-5-yl}methyl)pyr idinium (3 entities in total) |
| Functional Keywords | hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm: Q06124 |
| Total number of polymer chains | 1 |
| Total formula weight | 32655.06 |
| Authors | Zhang, Z.Y.,Yu, Z.H.,He, R.,Zhang, R.Y. (deposition date: 2014-09-18, release date: 2015-07-01, Last modification date: 2024-12-25) |
| Primary citation | He, R.,Yu, Z.H.,Zhang, R.Y.,Wu, L.,Gunawan, A.M.,Lane, B.S.,Shim, J.S.,Zeng, L.F.,He, Y.,Chen, L.,Wells, C.D.,Liu, J.O.,Zhang, Z.Y. Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors. ACS Med Chem Lett, 6:782-786, 2015 Cited by PubMed Abstract: Protein tyrosine phosphatases (PTPs) are potential therapeutic targets for many diseases. Unfortunately, despite considerable drug discovery efforts devoted to PTPs, obtaining selective and cell permeable PTP inhibitors remains highly challenging. We describe a strategy to explore the existing drug space for previously unknown PTP inhibitory activities. This led to the discovery of cefsulodin as an inhibitor of SHP2, an oncogenic phosphatase in the PTP family. Crystal structure analysis of SHP2 interaction with cefsulodin identified sulfophenyl acetic amide (SPAA) as a novel phosphotyrosine (pTyr) mimetic. A structure-guided and SPAA fragment-based focused library approach produced several potent and selective SHP2 inhibitors. Notably, these inhibitors blocked SHP2-mediated signaling events and proliferation in several cancer cell lines. Thus, SPAA may serve as a new platform for developing chemical probes for other PTPs. PubMed: 26191366DOI: 10.1021/acsmedchemlett.5b00118 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.601 Å) |
Structure validation
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