9B97

Crystal structure of the human PAD2 protein bound to small molecule

This is a non-PDB format compatible entry.

Summary for 9B97

• Entry DOI: 10.2210/pdb9b97/pdb
• Descriptor: Protein-arginine deiminase type-2, (4S)-2-METHYL-2,4-PENTANEDIOL, (1P)-N~3'~-[(2S)-3-cyclohexyl-1-(methylamino)-1-oxopropan-2-yl]-N~3~,N~3~-diethyl-4-fluoro-5'-{[4-(4-phenylbutyl)piperazin-1-yl]methyl}[1,1'-biphenyl]-3,3'-dicarboxamide, ... (6 entities in total)
• Functional Keywords: complex, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 79939.70

Authors

Byrnes, L.J.,Vajdos, F. (deposition date: 2024-04-01, release date: 2024-10-09, Last modification date: 2024-10-30)

Primary citation

Byrnes, L.J.,Choi, W.Y.,Balbo, P.,Banker, M.E.,Chang, J.,Chen, S.,Cheng, X.,Cong, Y.,Culp, J.,Di, H.,Griffor, M.,Hall, J.,Meng, X.,Morgan, B.,Mousseau, J.J.,Nicki, J.,O'Connell, T.,Ramsey, S.,Shaginian, A.,Shanker, S.,Trujillo, J.,Wan, J.,Vincent, F.,Wright, S.W.,Vajdos, F.
Discovery, Characterization, and Structure of a Cell Active PAD2 Inhibitor Acting through a Novel Allosteric Mechanism.
Acs Chem.Biol., 19:2186-2197, 2024

PubMed Abstract: Peptidyl arginine deiminases (PADs) are important enzymes in many diseases, especially those involving inflammation and autoimmunity. Despite many years of effort, developing isoform-specific inhibitors has been a challenge. We describe herein the discovery of a potent, noncovalent PAD2 inhibitor, with selectivity over PAD3 and PAD4, from a DNA-encoded library. The biochemical and biophysical characterization of this inhibitor and two noninhibitory binders indicated a novel, Ca competitive mechanism of inhibition. This was confirmed via X-ray crystallographic analysis. Finally, we demonstrate that this inhibitor selectively inhibits PAD2 in a cellular context.

PubMed: 39316753
DOI: 10.1021/acschembio.4c00397

Experimental method

X-RAY DIFFRACTION (1.95 Å)