2YOL

West Nile Virus NS2B-NS3 protease in complex with 3,4- dichlorophenylacetyl-Lys-Lys-GCMA

2YOL の概要

• エントリーDOI: 10.2210/pdb2yol/pdb
• 分子名称: SERINE PROTEASE SUBUNIT NS2B, SERINE PROTEASE NS3, CHLORIDE ION, (S)-6-amino-N-((S)-6-amino-1-(((1r,4S)-4-guanidinocyclohexyl)methylamino)-1-oxohexan-2-yl)-2-(2-(3,4-dichlorophenyl)acetamido)hexanamide, ... (5 entities in total)
• 機能のキーワード: serine protease, hydrolase, inhibitor
• 由来する生物種: WEST NILE VIRUS
• 細胞内の位置: Capsid protein C: Virion (Potential). Small envelope protein M: Virion membrane; Multi-pass membrane protein (By similarity). Envelope protein E: Virion membrane; Multi- pass membrane protein (By similarity). Non-structural protein 1: Secreted. Non-structural protein 2A: Host endoplasmic reticulum membrane; Multi-pass membrane protein (Potential). Serine protease subunit NS2B: Host endoplasmic reticulum membrane; Multi-pass membrane protein (Potential). Serine protease NS3: Host endoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic side (By similarity). Non-structural protein 4A: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Non-structural protein 4B: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). RNA-directed RNA polymerase NS5: Host endoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic side (By similarity): P06935
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25310.15

構造登録者

Hammamy, M.Z.,Haase, C.,Hammami, M.,Hilgenfeld, R.,Steinmetzer, T. (登録日: 2012-10-25, 公開日: 2013-03-27, 最終更新日: 2023-12-20)

主引用文献

Hammamy, M.Z.,Haase, C.,Hammami, M.,Hilgenfeld, R.,Steinmetzer, T.
Development and Characterization of New Peptidomimetic Inhibitors of the West Nile Virus Ns2B-Ns3 Protease.
Chemmedchem, 8:231-, 2013

PubMed Abstract: A series of new substrate analogue inhibitors of the WNV NS2B-NS3 protease containing decarboxylated arginine mimetics at the P1 position was developed. Among the various analogues, trans-(4-guanidino)cyclohexylmethylamide (GCMA) was identified as the most suitable P1 residue. In combination with dichloro-substituted phenylacetyl groups at the P4 position, three inhibitors with inhibition constants of <0.2 μM were obtained. These GCMA inhibitors have a better selectivity profile than the previously described agmatine analogues, and possess negligible affinity for the trypsin-like serine proteases thrombin, factor Xa, and matriptase. A crystal structure in complex with the WNV protease was determined for one of the most potent inhibitors, 3,4-dichlorophenylacetyl-Lys-Lys-GCMA (K(i)=0.13 μM). The inhibitor adopts a horseshoe-like conformation, most likely due to a hydrophobic contact between the P4 phenyl ring and the P1 cyclohexyl group, which is further stabilized by an intramolecular hydrogen bond between the P1 guanidino group and the P4 carbonyl oxygen atom. These inhibitors are stable, readily accessible, and have a noncovalent binding mode. Therefore, they may serve as suitable lead structures for further development.

PubMed: 23307694
DOI: 10.1002/CMDC.201200497

実験手法

X-RAY DIFFRACTION (3.2 Å)