2HAL

An episulfide cation (thiiranium ring) trapped in the active site of HAV 3C proteinase inactivated by peptide-based ketone inhibitors

2HAL の概要

• エントリーDOI: 10.2210/pdb2hal/pdb
• 関連するPDBエントリー: 1HAV 1QA7 2A4O 2CXV 2H6M 2H9H
• 関連するBIRD辞書のPRD_ID: PRD_000242
• 分子名称: Hepatitis A Protease 3C, N-ACETYL-LEUCYL-PHENYLALANYL-PHENYLALANYL-GLUTAMATE-FLUOROMETHYLKETONE INHIBITOR, N-[(BENZYLOXY)CARBONYL]-L-ALANINE, ... (4 entities in total)
• 機能のキーワード: hepatitis a virus, 3c protease, inhibitor design, methylketone, episulfide, picornain, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Hepatitis A virus
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 24110.77

構造登録者

Yin, J.,Cherney, M.M.,Bergmann, E.M.,James, M.N. (登録日: 2006-06-13, 公開日: 2006-08-08, 最終更新日: 2023-08-30)

主引用文献

Yin, J.,Cherney, M.M.,Bergmann, E.M.,Zhang, J.,Huitema, C.,Pettersson, H.,Eltis, L.D.,Vederas, J.C.,James, M.N.
An Episulfide Cation (Thiiranium Ring) Trapped in the Active Site of HAV 3C Proteinase Inactivated by Peptide-based Ketone Inhibitors.
J.Mol.Biol., 361:673-686, 2006

PubMed Abstract: We have solved the crystal and molecular structures of hepatitis A viral (HAV) 3C proteinase, a cysteine peptidase having a chymotrypsin-like protein fold, in complex with each of three tetrapeptidyl-based methyl ketone inhibitors to resolutions beyond 1.4 A, the highest resolution to date for a 3C or a 3C-Like (e.g. SARS viral main proteinase) peptidase. The residues of the beta-hairpin motif (residues 138-158), an extension of two beta-strands of the C-terminal beta-barrel of HAV 3C are critical for the interactions between the enzyme and the tetrapeptide portion of these inhibitors that are analogous to the residues at the P4 to P1 positions in the natural substrates of picornaviral 3C proteinases. Unexpectedly, the Sgamma of Cys172 forms two covalent bonds with each inhibitor, yielding an unusual episulfide cation (thiiranium ring) stabilized by a nearby oxyanion. This result suggests a mechanism of inactivation of 3C peptidases by methyl ketone inhibitors that is distinct from that occurring in the structurally related serine proteinases or in the papain-like cysteine peptidases. It also provides insight into the mechanisms underlying both the inactivation of HAV 3C by these inhibitors and on the proteolysis of natural substrates by this viral cysteine peptidase.

PubMed: 16860823
DOI: 10.1016/j.jmb.2006.06.047

実験手法

X-RAY DIFFRACTION (1.35 Å)