3B1U

Crystal structure of human peptidylarginine deiminase 4 in complex with o-F-amidine

Summary for 3B1U

• Entry DOI: 10.2210/pdb3b1u/pdb
• Related: 3B1T
• Descriptor: Protein-arginine deiminase type-4, 2-{[(2S)-1-amino-5-{[(1Z)-2-fluoroethanimidoyl]amino}-1-oxopentan-2-yl]carbamoyl}benzoic acid, SULFATE ION, ... (5 entities in total)
• Functional Keywords: nuclei, 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: 75792.81

Authors

Causey, C.P.,Jones, J.E.,Slack, J.L.,Kamei, D.,Jones Jr, L.E.,Subramanian, V.,Knuckley, B.,Ebrahimi, P.,Chumanevich, A.A.,Luo, Y.,Hashimoto, H.,Shimizu, T.,Sato, M.,Hofseth, L.J.,Thompson, P.R. (deposition date: 2011-07-13, release date: 2011-10-26, Last modification date: 2024-10-16)

Primary citation

Causey, C.P.,Jones, J.E.,Slack, J.L.,Kamei, D.,Jones Jr, L.E.,Subramanian, V.,Knuckley, B.,Ebrahimi, P.,Chumanevich, A.A.,Luo, Y.,Hashimoto, H.,Sato, M.,Hofseth, L.J.,Thompson, P.R.
The Development of N-alpha-(2-Carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine Amide (o-F-amidine) and N-alpha-(2-Carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine Amide (o-Cl-amidine) As Second Generation Protein Arginine Deiminase (PAD) Inhibitors
J.Med.Chem., 54:6919-6935, 2011

PubMed Abstract: Protein arginine deiminase (PAD) activity is upregulated in a number of human diseases, including rheumatoid arthritis, ulcerative colitis, and cancer. These enzymes, there are five in humans (PADs 1-4 and 6), regulate gene transcription, cellular differentiation, and the innate immune response. Building on our successful generation of F- and Cl-amidine, which irreversibly inhibit all of the PADs, a structure-activity relationship was performed to develop second generation compounds with improved potency and selectivity. Incorporation of a carboxylate ortho to the backbone amide resulted in the identification of N-α-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-α-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine), as PAD inactivators with improved potency (up to 65-fold) and selectivity (up to 25-fold). Relative to F- and Cl-amidine, the compounds also show enhanced potency in cellulo. As such, these compounds will be versatile chemical probes of PAD function.

PubMed: 21882827
DOI: 10.1021/jm2008985

Experimental method

X-RAY DIFFRACTION (2.1 Å)