PDBsum entry 4n2e

Hydrolase

PDB id: 4n2e

Contents

Protein chain

653 a.a.

Ligands

MPD ×4

Metals

_CA ×5

Waters ×609

PDB id:

4n2e

Name:

Hydrolase

Title:

Crystal structure of protein arginine deiminase 2 (d123n, 10 mm ca2+)

Structure:

Protein-arginine deiminase type-2. Chain: a. Synonym: pad-h19, peptidylarginine deiminase ii, protein-arginine deiminase type ii. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: padi2, kiaa0994, pdi2. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.86Å R-factor: 0.171 R-free: 0.208

Authors:

D.J.Slade,X.Zhang,P.Fang,C.J.Dreyton,Y.Zhang,M.L.Gross,M.Guo, S.A.Coonrod,P.R.Thompson

Key ref:

D.J.Slade et al. (2015). Protein arginine deiminase 2 binds calcium in an ordered fashion: implications for inhibitor design. Acs Chem Biol, 10, 1043-1053. PubMed id: 25621824 DOI: 10.1021/cb500933j

Date:

04-Oct-13 Release date: 04-Feb-15

Protein chain

Q9Y2J8  (PADI2_HUMAN) -  Protein-arginine deiminase type-2 from Homo sapiens

Seq: 665 a.a.

Struc: 653 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.5.3.15 - protein-arginine deiminase.
• Reaction: L-arginyl-[protein] + H2O = L-citrullyl-[protein] + NH4⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/cb500933j

Acs Chem Biol 10:1043-1053 (2015)

PubMed id: 25621824

Protein arginine deiminase 2 binds calcium in an ordered fashion: implications for inhibitor design.

D.J.Slade, P.Fang, C.J.Dreyton, Y.Zhang, J.Fuhrmann, D.Rempel, B.D.Bax, S.A.Coonrod, H.D.Lewis, M.Guo, M.L.Gross, P.R.Thompson.

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.