9lg2

Phosphoglycerate mutase 1 complexed with a covalent inhibitor

spinqualitylabelsall models 9lg2, resolution 2.02Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9lg2 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.02Å Ligands: A1EJR, CL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PGAM1_HUMAN Interconversion of 3- and 2-phosphoglycerate with 2,3-bisphosphoglycerate as the primer of the reaction. Can also catalyze the reaction of EC 5.4.2.4 (synthase) and EC 3.1.3.13 (phosphatase), but with a reduced activity. Publication Abstract from PubMed Broadening the application of covalent inhibitors requires the exploration of nucleophilic residues beyond cysteine. The covalent DNA-encoded chemical library (CoDEL) represents an advanced technology for covalent drug discovery. However, its application in lysine-targeting inhibitors remains uncharted territory. Here, we report the utilization of CoDEL selection guided by proteome-wide data to identify lysine-targeting covalent inhibitors. A comprehensive assessment of activity-based protein profiling (ABPP) data on lysine distribution and ligandability reveals potential targets for selective covalent inhibition, including phosphoglycerate mutase 1 (PGAM1), bromodomain (BRD) family proteins, and ubiquitin-conjugating enzyme E2 N (UBE2N). The 10.7-million-member CoDELs, featuring diverse lysine-reactive warheads, enable the discovery of a series of covalent inhibitors, covering photo-covalent, reversible covalent, and irreversible covalent reaction mechanisms. In-depth characterization of binding sites and modes of action provides structural and functional insights. Notably, irreversible covalent inhibitors unveil a novel mechanism for regulating UBE2N-mediated ubiquitination by modulating the conformation of the protein complex. Our work adopts the ABPP-CoDEL strategy, offering an efficient and versatile selection method for the development of covalent inhibitors targeting functional lysines. Proteome-Wide Data Guides the Discovery of Lysine-Targeting Covalent Inhibitors Using DNA-Encoded Chemical Libraries.,Wu X, Li S, Liang T, Yu Q, Zhang Y, Liu J, Li K, Liu Z, Cui M, Zhao Y, Han X, Jin R, Tan M, Chen XH, Zhao Y, Zheng M, Sun Y, Zhou L, Lu X Angew Chem Int Ed Engl. 2025 Apr 13:e202505581. doi: 10.1002/anie.202505581. PMID:40223230 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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