2YOL
West Nile Virus NS2B-NS3 protease in complex with 3,4- dichlorophenylacetyl-Lys-Lys-GCMA
Summary for 2YOL
| Entry DOI | 10.2210/pdb2yol/pdb |
| Descriptor | 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) |
| Functional Keywords | serine protease, hydrolase, inhibitor |
| Biological source | WEST NILE VIRUS |
| Cellular location | 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 |
| Total number of polymer chains | 1 |
| Total formula weight | 25310.15 |
| Authors | Hammamy, M.Z.,Haase, C.,Hammami, M.,Hilgenfeld, R.,Steinmetzer, T. (deposition date: 2012-10-25, release date: 2013-03-27, Last modification date: 2023-12-20) |
| Primary citation | 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 Cited by 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: 23307694DOI: 10.1002/CMDC.201200497 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.2 Å) |
Structure validation
Download full validation report
