9TKT
Mapping the SHP2 allosteric pocket with target-biased covalent fragments
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Summary for 9TKT
| Entry DOI | 10.2210/pdb9tkt/pdb |
| Descriptor | Tyrosine-protein phosphatase non-receptor type 11, 1,2-ETHANEDIOL, 3-[(1S)-1-azanylspiro[1,3-dihydroindene-2,4'-piperidine]-1'-yl]carbonylbenzenesulfonic acid, ... (4 entities in total) |
| Functional Keywords | shp2 allosteric site, aryl sulfonyl fluoride warheads, sf12a, cytosolic protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 120806.19 |
| Authors | |
| Primary citation | Efrem, N.L.,Csorba, N.,Amoussa, M.,Abranyi-Balogh, P.,Guo, Z.,Petri, L.,Bo, F.,Di Lorenzo, V.,Roske, Y.,Szalai, T.V.,Mihalovits, L.,Simon, J.,Li, J.,Daumke, O.,Keseru, G.M.,Nazare, M. Mapping the SHP2 Allosteric Pocket With Target-Biased Covalent Fragments. Chembiochem, 27:e70310-e70310, 2026 Cited by PubMed Abstract: Targeted covalent inhibitors (TCIs) form covalent bonds with a specific amino acid in their target proteins, offering high selectivity and sustained pharmacologic effects. However, identifying optimal electrophilic warheads and nucleophilic amino acids remains a major hurdle for TCI development. While covalent fragment libraries are efficient in the identification of reactive residues, their inherently weak and transient interactions often fail to address functionally relevant binding sites. Here, we combine the exploratory approach of covalent fragment screening with established inhibitor pharmacophores for covalent mapping of the tunnel allosteric site of the oncogenic phosphatase SHP2. Aryl sulfonyl fluoride (SF) fragments featuring pharmacophore elements to enhance noncovalent interactions (target-biased fragments) covalently targeted lysine 492 (K492) in the tunnel binding site, while a conventional SF fragment library lacking these features was not reactive toward K492. Covalent engagement of K492 improved enzyme inhibition and provides a starting point for SHP2 TCI development. More broadly, this study underscores how noncovalent interactions direct covalent fragment binding and highlights target-biased fragments as a complementary strategy to conventional covalent fragment libraries to identify suitable warheads and reactive amino acids in functionally relevant binding sites with minimal a priori knowledge of ligand pharmacophores. PubMed: 42033018DOI: 10.1002/cbic.70310 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.35 Å) |
Structure validation
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