4M9F
Dengue virus NS2B-NS3 protease A125C variant at pH 8.5
Summary for 4M9F
| Entry DOI | 10.2210/pdb4m9f/pdb |
| Related | 2fom 3U1I 3U1J 4M9I 4M9K 4M9M 4M9T |
| Descriptor | NS2B-NS3 protease (2 entities in total) |
| Functional Keywords | serine protease, allosteric inhibition, dengue virus protease, trypsin-like protease, conformational flexibility, viral protein |
| Biological source | Dengue virus 2 More |
| Cellular location | Virion membrane ; Multi-pass membrane protein : Q91H74 |
| Total number of polymer chains | 1 |
| Total formula weight | 26360.48 |
| Authors | Yildiz, M.,Ghosh, S.,Bell, J.A.,Sherman, W.,Hardy, J.A. (deposition date: 2013-08-14, release date: 2013-11-27, Last modification date: 2023-09-20) |
| Primary citation | Yildiz, M.,Ghosh, S.,Bell, J.A.,Sherman, W.,Hardy, J.A. Allosteric Inhibition of the NS2B-NS3 Protease from Dengue Virus. Acs Chem.Biol., 8:2744-2752, 2013 Cited by PubMed Abstract: Dengue virus is the flavivirus that causes dengue fever, dengue hemorrhagic disease, and dengue shock syndrome, which are currently increasing in incidence worldwide. Dengue virus protease (NS2B-NS3pro) is essential for dengue virus infection and is thus a target of therapeutic interest. To date, attention has focused on developing active-site inhibitors of NS2B-NS3pro. The flat and charged nature of the NS2B-NS3pro active site may contribute to difficulties in developing inhibitors and suggests that a strategy of identifying allosteric sites may be useful. We report an approach that allowed us to scan the NS2B-NS3pro surface by cysteine mutagenesis and use cysteine reactive probes to identify regions of the protein that are susceptible to allosteric inhibition. This method identified a new allosteric site utilizing a circumscribed panel of just eight cysteine variants and only five cysteine reactive probes. The allosterically sensitive site is centered at Ala125, between the 120s loop and the 150s loop. The crystal structures of WT and modified NS2B-NS3pro demonstrate that the 120s loop is flexible. Our work suggests that binding at this site prevents a conformational rearrangement of the NS2B region of the protein, which is required for activation. Preventing this movement locks the protein into the open, inactive conformation, suggesting that this site may be useful in the future development of therapeutic allosteric inhibitors. PubMed: 24164286DOI: 10.1021/cb400612h PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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