4N2L

Crystal structure of Protein Arginine Deiminase 2 (Q350A, 10 mM Ca2+)

Summary for 4N2L

• Entry DOI: 10.2210/pdb4n2l/pdb
• Related: 4N20 4N22 4N24 4N25 4N26 4N28 4N2A 4N2B 4N2C 4N2D 4N2E 4N2F 4N2G 4N2H 4N2I 4N2K 4N2M 4N2N
• Descriptor: Protein-arginine deiminase type-2, (4S)-2-METHYL-2,4-PENTANEDIOL, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: deiminase, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : Q9Y2J8
• Total number of polymer chains: 1
• Total formula weight: 79702.43

Authors

Slade, D.J.,Zhang, X.,Fang, P.,Dreyton, C.J.,Zhang, Y.,Gross, M.L.,Guo, M.,Coonrod, S.A.,Thompson, P.R. (deposition date: 2013-10-05, release date: 2015-02-04, Last modification date: 2023-09-20)

Primary citation

Slade, D.J.,Fang, P.,Dreyton, C.J.,Zhang, Y.,Fuhrmann, J.,Rempel, D.,Bax, B.D.,Coonrod, S.A.,Lewis, H.D.,Guo, M.,Gross, M.L.,Thompson, P.R.
Protein arginine deiminase 2 binds calcium in an ordered fashion: implications for inhibitor design.
Acs Chem.Biol., 10:1043-1053, 2015

PubMed Abstract: Protein arginine deiminases (PADs) are calcium-dependent histone-modifying enzymes whose activity is dysregulated in inflammatory diseases and cancer. PAD2 functions as an Estrogen Receptor (ER) coactivator in breast cancer cells via the citrullination of histone tail arginine residues at ER binding sites. Although an attractive therapeutic target, the mechanisms that regulate PAD2 activity are largely unknown, especially the detailed role of how calcium facilitates enzyme activation. To gain insights into these regulatory processes, we determined the first structures of PAD2 (27 in total), and through calcium-titrations by X-ray crystallography, determined the order of binding and affinity for the six calcium ions that bind and activate this enzyme. These structures also identified several PAD2 regulatory elements, including a calcium switch that controls proper positioning of the catalytic cysteine residue, and a novel active site shielding mechanism. Additional biochemical and mass-spectrometry-based hydrogen/deuterium exchange studies support these structural findings. The identification of multiple intermediate calcium-bound structures along the PAD2 activation pathway provides critical insights that will aid the development of allosteric inhibitors targeting the PADs.

PubMed: 25621824
DOI: 10.1021/cb500933j

Experimental method

X-RAY DIFFRACTION (2.1 Å)