5N0Y

hPAD4 crystal complex with AFM-30a

Summary for 5N0Y

• Entry DOI: 10.2210/pdb5n0y/pdb
• Related: 5N0M
• Descriptor: Protein-arginine deiminase type-4, SULFATE ION, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q9UM07
• Total number of polymer chains: 1
• Total formula weight: 75676.77

Authors

Beaumont, E.,Kerry, P.,Thompson, P.,Muth, A.,Subramanian, V.,Nagar, M.,Srinath, H.,Clancy, K.,Parelkar, S. (deposition date: 2017-02-03, release date: 2017-05-24, Last modification date: 2024-11-20)

Primary citation

Muth, A.,Subramanian, V.,Beaumont, E.,Nagar, M.,Kerry, P.,McEwan, P.,Srinath, H.,Clancy, K.,Parelkar, S.,Thompson, P.R.
Development of a Selective Inhibitor of Protein Arginine Deiminase 2.
J. Med. Chem., 60:3198-3211, 2017

PubMed Abstract: Protein arginine deiminase 2 (PAD2) plays a key role in the onset and progression of multiple sclerosis, rheumatoid arthritis, and breast cancer. To date, no PAD2-selective inhibitor has been developed. Such a compound will be critical for elucidating the biological roles of this isozyme and may ultimately be useful for treating specific diseases in which PAD2 activity is dysregulated. To achieve this goal, we synthesized a series of benzimidazole-based derivatives of Cl-amidine, hypothesizing that this scaffold would allow access to a series of PAD2-selective inhibitors with enhanced cellular efficacy. Herein, we demonstrate that substitutions at both the N-terminus and C-terminus of Cl-amidine result in >100-fold increases in PAD2 potency and selectivity (30a, 41a, and 49a) as well as cellular efficacy (30a). Notably, these compounds use the far less reactive fluoroacetamidine warhead. In total, we predict that 30a will be a critical tool for understanding cellular PAD2 function and sets the stage for treating diseases in which PAD2 activity is dysregulated.

PubMed: 28328217
DOI: 10.1021/acs.jmedchem.7b00274

Experimental method

X-RAY DIFFRACTION (2.23 Å)