8su8 | pdb_00008su8

Co-crystal structure of KRIT1 with a 1-hydroxy 2-naphthaldehyde derivative (6-(furan-2-yl)-2-hydroxy-1-naphthaldehyde).

spinqualitylabelsall models 8su8, resolution 2.01Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8su8 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 2.01Å Ligands: GNP, MG, XE2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function RAP1B_HUMAN GTP-binding protein that possesses intrinsic GTPase activity. Contributes to the polarizing activity of KRIT1 and CDH5 in the establishment and maintenance of correct endothelial cell polarity and vascular lumen. Required for the localization of phosphorylated PRKCZ, PARD3 and TIAM1 to the cell junction. Publication Abstract from PubMed The covalent reversible modification of proteins is a validated strategy for the development of probes and candidate therapeutics. However, the covalent reversible targeting of noncatalytic lysines is particularly challenging. Herein, we characterize the 2-hydroxy-1-naphthaldehyde (HNA) fragment as a targeted covalent reversible ligand of a noncatalytic lysine (Lys(720)) of the Krev interaction trapped 1 (KRIT1) protein. We show that the interaction of HNA with KRIT1 is highly specific, results in prolonged residence time of >8 h, and inhibits the Heart of glass 1 (HEG1)-KRIT1 protein-protein interaction (PPI). Screening of HNA derivatives identified analogs exhibiting similar binding modes as the parent fragment but faster target engagement and stronger inhibition activity. These results demonstrate that HNA is an efficient site-directing fragment with promise in developing HEG1-KRIT1 PPI inhibitors. Further, the aldimine chemistry, when coupled with templating effects that promote proximity, can produce a long-lasting reversible covalent modification of noncatalytic lysines. Targeted Reversible Covalent Modification of a Noncatalytic Lysine of the Krev Interaction Trapped 1 Protein Enables Site-Directed Screening for Protein-Protein Interaction Inhibitors.,Francisco KR, Bruystens J, Varricchio C, McCurdy S, Wu J, Lopez-Ramirez MA, Ginsberg M, Caffrey CR, Brancale A, Gingras AR, Hixon MS, Ballatore C ACS Pharmacol Transl Sci. 2023 Oct 9;6(11):1651-1658. doi: , 10.1021/acsptsci.3c00156. eCollection 2023 Nov 10. PMID:37974623 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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