8T7V

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

Summary for 8T7V

• Entry DOI: 10.2210/pdb8t7v/pdb
• Related: 8SU8 8T09
• Descriptor: Krev interaction trapped protein 1, Ras-related protein Rap-1b, (7M)-7-(furan-2-yl)-2-hydroxynaphthalene-1-carbaldehyde, ... (6 entities in total)
• Functional Keywords: complex, inhibitor, cell adhesion
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 57049.47

Authors

Bruystens, J.G.H. (deposition date: 2023-06-21, release date: 2023-12-06, Last modification date: 2024-11-06)

Primary citation

Francisco, K.R.,Bruystens, J.,Varricchio, C.,McCurdy, S.,Wu, J.,Lopez-Ramirez, M.A.,Ginsberg, M.,Caffrey, C.R.,Brancale, A.,Gingras, A.R.,Hixon, M.S.,Ballatore, C.
Targeted Reversible Covalent Modification of a Noncatalytic Lysine of the Krev Interaction Trapped 1 Protein Enables Site-Directed Screening for Protein-Protein Interaction Inhibitors.
Acs Pharmacol Transl Sci, 6:1651-1658, 2023

PubMed Abstract: 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) 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.

PubMed: 37974623
DOI: 10.1021/acsptsci.3c00156

Experimental method

X-RAY DIFFRACTION (2.25 Å)