4BOF

Crystal structure of arginine deiminase from group A streptococcus

4BOF の概要

• エントリーDOI: 10.2210/pdb4bof/pdb
• 分子名称: ARGININE DEIMINASE, SULFATE ION, TRIETHYLENE GLYCOL, ... (5 entities in total)
• 機能のキーワード: hydrolase, vaccine
• 由来する生物種: STREPTOCOCCUS PYOGENES
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 372852.99

構造登録者

Henningham, A.,Ericsson, D.J.,Langer, K.,Casey, L.,Jovcevski, B.,Chhatwal, G.S.,Aquilina, J.A.,Batzloff, M.R.,Kobe, B.,Walker, M.J. (登録日: 2013-05-20, 公開日: 2013-08-21, 最終更新日: 2023-12-20)

主引用文献

Henningham, A.,Ericsson, D.J.,Langer, K.,Casey, L.W.,Jovcevski, B.,Chhatwal, G.S.,Aquilina, J.A.,Batzloff, M.R.,Kobe, B.,Walker, M.J.
Structure-informed design of an enzymatically inactive vaccine component for group A Streptococcus.
MBio, 4:-, 2013

PubMed Abstract: Streptococcus pyogenes (group A Streptococcus [GAS]) causes ~700 million human infections/year, resulting in >500,000 deaths. There is no commercial GAS vaccine available. The GAS surface protein arginine deiminase (ADI) protects mice against a lethal challenge. ADI is an enzyme that converts arginine to citrulline and ammonia. Administration of a GAS vaccine preparation containing wild-type ADI, a protein with inherent enzymatic activity, may present a safety risk. In an approach intended to maximize the vaccine safety of GAS ADI, X-ray crystallography and structural immunogenic epitope mapping were used to inform vaccine design. This study aimed to knock out ADI enzyme activity without disrupting the three-dimensional structure or the recognition of immunogenic epitopes. We determined the crystal structure of ADI at 2.5 Å resolution and used it to select a number of amino acid residues for mutagenesis to alanine (D166, E220, H275, D277, and C401). Each mutant protein displayed abrogated activity, and three of the mutant proteins (those with the D166A, H275A, and D277A mutations) possessed a secondary structure and oligomerization state equivalent to those of the wild type, produced high-titer antisera, and avoided disruption of B-cell epitopes of ADI. In addition, antisera raised against the D166A and D277A mutant proteins bound to the GAS cell surface. The inactivated D166A and D277A mutant ADIs are ideal for inclusion in a GAS vaccine preparation. There is no human ortholog of ADI, and we confirm that despite limited structural similarity in the active-site region to human peptidyl ADI 4 (PAD4), ADI does not functionally mimic PAD4 and antiserum raised against GAS ADI does not recognize human PAD4.

PubMed: 23919999
DOI: 10.1128/mBio.00509-13

実験手法

X-RAY DIFFRACTION (2.48 Å)