5F1V

biomimetic design results in a potent allosteric inhibitor of dihydrodipicolinate synthase from Campylobacter jejuni

5F1V の概要

• エントリーDOI: 10.2210/pdb5f1v/pdb
• 関連するPDBエントリー: 5F1U
• 分子名称: 4-hydroxy-tetrahydrodipicolinate synthase, (2R,5R)-2,5-diamino-2,5-bis(4-aminobutyl)hexanedioic acid, TRIETHYLENE GLYCOL, ... (6 entities in total)
• 機能のキーワード: schiff-base, aldolase, tim barrel, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• 由来する生物種: Campylobacter jejuni
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 132969.05

構造登録者

Conly, C.J.T.,Palmer, D.R.J.,Sanders, D.A.R. (登録日: 2015-11-30, 公開日: 2016-02-17, 最終更新日: 2023-11-29)

主引用文献

Skovpen, Y.V.,Conly, C.J.,Sanders, D.A.,Palmer, D.R.
Biomimetic Design Results in a Potent Allosteric Inhibitor of Dihydrodipicolinate Synthase from Campylobacter jejuni.
J.Am.Chem.Soc., 138:2014-2020, 2016

PubMed Abstract: Dihydrodipicolinate synthase (DHDPS), an enzyme required for bacterial peptidoglycan biosynthesis, catalyzes the condensation of pyruvate and β-aspartate semialdehyde (ASA) to form a cyclic product which dehydrates to form dihydrodipicolinate. DHDPS has, for several years, been considered a putative target for novel antibiotics. We have designed the first potent inhibitor of this enzyme by mimicking its natural allosteric regulation by lysine, and obtained a crystal structure of the protein-inhibitor complex at 2.2 Å resolution. This novel inhibitor, which we named "bislysine", resembles two lysine molecules linked by an ethylene bridge between the α-carbon atoms. Bislysine is a mixed partial inhibitor with respect to the first substrate, pyruvate, and a noncompetitive partial inhibitor with respect to ASA, and binds to all forms of the enzyme with a Ki near 200 nM, more than 300 times more tightly than lysine. Hill plots show that the inhibition is cooperative, indicating that the allosteric sites are not independent despite being located on opposite sides of the protein tetramer, separated by approximately 50 Å. A mutant enzyme resistant to lysine inhibition, Y110F, is strongly inhibited by this novel inhibitor, suggesting this may be a promising strategy for antibiotic development.

PubMed: 26836694
DOI: 10.1021/jacs.5b12695

実験手法

X-RAY DIFFRACTION (2.2 Å)