|
|
| (2 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==1.90 A resolution structure of Norovirus 3CL protease in complex with the dipeptidyl inhibitor 7l (orthorhombic P form)== | | ==1.90 A resolution structure of Norovirus 3CL protease in complex with the dipeptidyl inhibitor 7l (orthorhombic P form)== |
| - | <StructureSection load='5t6f' size='340' side='right' caption='[[5t6f]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='5t6f' size='340' side='right'caption='[[5t6f]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5t6f]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T6F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5T6F FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5t6f]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Norovirus_Hu/1968/US Norovirus Hu/1968/US]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T6F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5T6F FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=N38:3-CYCLOHEXYL-N-{(2S)-1-HYDROXY-3-[(3S)-2-OXOPYRROLIDIN-3-YL]PROPAN-2-YL}-N~2~-{[3-(4-METHOXYPHENOXY)PROPYL]SULFONYL}-L-ALANINAMIDE'>N38</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5t6d|5t6d]], [[5t6g|5t6g]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=N38:3-CYCLOHEXYL-N-{(2S)-1-HYDROXY-3-[(3S)-2-OXOPYRROLIDIN-3-YL]PROPAN-2-YL}-N~2~-{[3-(4-METHOXYPHENOXY)PROPYL]SULFONYL}-L-ALANINAMIDE'>N38</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5t6f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t6f OCA], [http://pdbe.org/5t6f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5t6f RCSB], [http://www.ebi.ac.uk/pdbsum/5t6f PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5t6f ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5t6f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t6f OCA], [https://pdbe.org/5t6f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5t6f RCSB], [https://www.ebi.ac.uk/pdbsum/5t6f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5t6f ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/POLG_NVN68 POLG_NVN68]] Protein p48 may play a role in viral replication by interacting with host VAPA, a vesicle-associated membrane protein that plays a role in SNARE-mediated vesicle fusion. This interaction may target replication complex to intracellular membranes.<ref>PMID:569187</ref> <ref>PMID:11160659</ref> NTPase presumably plays a role in replication. Despite having similarities with helicases, does not seem to display any helicase activity.<ref>PMID:569187</ref> <ref>PMID:11160659</ref> Protein P22 may play a role in targeting replication complex to intracellular membranes.<ref>PMID:569187</ref> <ref>PMID:11160659</ref> Viral genome-linked protein is covalently linked to the 5'-end of the positive-strand, negative-strand genomic RNAs and subgenomic RNA. Acts as a genome-linked replication primer. May recruit ribosome to viral RNA thereby promoting viral proteins translation.<ref>PMID:569187</ref> <ref>PMID:11160659</ref> 3C-like protease processes the polyprotein: 3CLpro-RdRp is first released by autocleavage, then all other proteins are cleaved. May cleave host polyadenylate-binding protein thereby inhibiting cellular translation (By similarity).<ref>PMID:569187</ref> <ref>PMID:11160659</ref> RNA-directed RNA polymerase replicates genomic and antigenomic RNA by recognizing replications specific signals. Transcribes also a subgenomic mRNA by initiating RNA synthesis internally on antigenomic RNA. This sgRNA encodes for structural proteins. Catalyzes the covalent attachment VPg with viral RNAs (By similarity).<ref>PMID:569187</ref> <ref>PMID:11160659</ref> | + | [https://www.uniprot.org/uniprot/POLG_NVN68 POLG_NVN68] Protein p48 may play a role in viral replication by interacting with host VAPA, a vesicle-associated membrane protein that plays a role in SNARE-mediated vesicle fusion. This interaction may target replication complex to intracellular membranes.<ref>PMID:569187</ref> <ref>PMID:11160659</ref> NTPase presumably plays a role in replication. Despite having similarities with helicases, does not seem to display any helicase activity.<ref>PMID:569187</ref> <ref>PMID:11160659</ref> Protein P22 may play a role in targeting replication complex to intracellular membranes.<ref>PMID:569187</ref> <ref>PMID:11160659</ref> Viral genome-linked protein is covalently linked to the 5'-end of the positive-strand, negative-strand genomic RNAs and subgenomic RNA. Acts as a genome-linked replication primer. May recruit ribosome to viral RNA thereby promoting viral proteins translation.<ref>PMID:569187</ref> <ref>PMID:11160659</ref> 3C-like protease processes the polyprotein: 3CLpro-RdRp is first released by autocleavage, then all other proteins are cleaved. May cleave host polyadenylate-binding protein thereby inhibiting cellular translation (By similarity).<ref>PMID:569187</ref> <ref>PMID:11160659</ref> RNA-directed RNA polymerase replicates genomic and antigenomic RNA by recognizing replications specific signals. Transcribes also a subgenomic mRNA by initiating RNA synthesis internally on antigenomic RNA. This sgRNA encodes for structural proteins. Catalyzes the covalent attachment VPg with viral RNAs (By similarity).<ref>PMID:569187</ref> <ref>PMID:11160659</ref> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Human noroviruses are the primary cause of epidemic and sporadic acute gastroenteritis. The worldwide high morbidity and mortality associated with norovirus infections, particularly among the elderly, immunocompromised patients and children, constitute a serious public health concern. There are currently no approved human vaccines or norovirus-specific small-molecule therapeutics or prophylactics. Norovirus 3CL protease has recently emerged as a potential therapeutic target for the development of anti-norovirus agents. We hypothesized that the S4 subsite of the enzyme may provide an effective means of designing potent and cell permeable inhibitors of the enzyme. We report herein the structure-guided exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design and synthesis of effective inhibitors of the protease. |
| | + | |
| | + | Structure-based exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design of potent and permeable inhibitors.,Galasiti Kankanamalage AC, Kim Y, Rathnayake AD, Damalanka VC, Weerawarna PM, Doyle ST, Alsoudi AF, Dissanayake DM, Lushington GH, Mehzabeen N, Battaile KP, Lovell S, Chang KO, Groutas WC Eur J Med Chem. 2016 Nov 14;126:502-516. doi: 10.1016/j.ejmech.2016.11.027. PMID:27914364<ref>PMID:27914364</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 5t6f" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Virus protease 3D structures|Virus protease 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Alsoudi, A F]] | + | [[Category: Large Structures]] |
| - | [[Category: Battaile, K P]] | + | [[Category: Norovirus Hu/1968/US]] |
| - | [[Category: Chang, K O]] | + | [[Category: Alsoudi AF]] |
| - | [[Category: Damalanka, V C]] | + | [[Category: Battaile KP]] |
| - | [[Category: Dissanayake, D M.P]] | + | [[Category: Chang K-O]] |
| - | [[Category: Doyle, S T]] | + | [[Category: Damalanka VC]] |
| - | [[Category: Groutas, W C]] | + | [[Category: Dissanayake DMP]] |
| - | [[Category: Kankanamalage, A C.G]] | + | [[Category: Doyle ST]] |
| - | [[Category: Kim, Y]] | + | [[Category: Groutas WC]] |
| - | [[Category: Lovell, S]] | + | [[Category: Kankanamalage ACG]] |
| - | [[Category: Mehzabeen, N]] | + | [[Category: Kim Y]] |
| - | [[Category: Rathnayake, A D]] | + | [[Category: Lovell S]] |
| - | [[Category: Weerawarna, P M]] | + | [[Category: Mehzabeen N]] |
| - | [[Category: Antiviral inhibitor]]
| + | [[Category: Rathnayake AD]] |
| - | [[Category: Dipeptidyl inhibitor]]
| + | [[Category: Weerawarna PM]] |
| - | [[Category: Norovirus]]
| + | |
| - | [[Category: Norwalk virus]]
| + | |
| - | [[Category: Protease]]
| + | |
| - | [[Category: Protease-protease inhibitor complex]]
| + | |
| Structural highlights
Function
POLG_NVN68 Protein p48 may play a role in viral replication by interacting with host VAPA, a vesicle-associated membrane protein that plays a role in SNARE-mediated vesicle fusion. This interaction may target replication complex to intracellular membranes.[1] [2] NTPase presumably plays a role in replication. Despite having similarities with helicases, does not seem to display any helicase activity.[3] [4] Protein P22 may play a role in targeting replication complex to intracellular membranes.[5] [6] Viral genome-linked protein is covalently linked to the 5'-end of the positive-strand, negative-strand genomic RNAs and subgenomic RNA. Acts as a genome-linked replication primer. May recruit ribosome to viral RNA thereby promoting viral proteins translation.[7] [8] 3C-like protease processes the polyprotein: 3CLpro-RdRp is first released by autocleavage, then all other proteins are cleaved. May cleave host polyadenylate-binding protein thereby inhibiting cellular translation (By similarity).[9] [10] RNA-directed RNA polymerase replicates genomic and antigenomic RNA by recognizing replications specific signals. Transcribes also a subgenomic mRNA by initiating RNA synthesis internally on antigenomic RNA. This sgRNA encodes for structural proteins. Catalyzes the covalent attachment VPg with viral RNAs (By similarity).[11] [12]
Publication Abstract from PubMed
Human noroviruses are the primary cause of epidemic and sporadic acute gastroenteritis. The worldwide high morbidity and mortality associated with norovirus infections, particularly among the elderly, immunocompromised patients and children, constitute a serious public health concern. There are currently no approved human vaccines or norovirus-specific small-molecule therapeutics or prophylactics. Norovirus 3CL protease has recently emerged as a potential therapeutic target for the development of anti-norovirus agents. We hypothesized that the S4 subsite of the enzyme may provide an effective means of designing potent and cell permeable inhibitors of the enzyme. We report herein the structure-guided exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design and synthesis of effective inhibitors of the protease.
Structure-based exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design of potent and permeable inhibitors.,Galasiti Kankanamalage AC, Kim Y, Rathnayake AD, Damalanka VC, Weerawarna PM, Doyle ST, Alsoudi AF, Dissanayake DM, Lushington GH, Mehzabeen N, Battaile KP, Lovell S, Chang KO, Groutas WC Eur J Med Chem. 2016 Nov 14;126:502-516. doi: 10.1016/j.ejmech.2016.11.027. PMID:27914364[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Burroughs JN, Brown F. Presence of a covalently linked protein on calicivirus RNA. J Gen Virol. 1978 Nov;41(2):443-6. PMID:569187
- ↑ Pfister T, Wimmer E. Polypeptide p41 of a Norwalk-like virus is a nucleic acid-independent nucleoside triphosphatase. J Virol. 2001 Feb;75(4):1611-9. PMID:11160659 doi:10.1128/JVI.75.4.1611-1619.2001
- ↑ Burroughs JN, Brown F. Presence of a covalently linked protein on calicivirus RNA. J Gen Virol. 1978 Nov;41(2):443-6. PMID:569187
- ↑ Pfister T, Wimmer E. Polypeptide p41 of a Norwalk-like virus is a nucleic acid-independent nucleoside triphosphatase. J Virol. 2001 Feb;75(4):1611-9. PMID:11160659 doi:10.1128/JVI.75.4.1611-1619.2001
- ↑ Burroughs JN, Brown F. Presence of a covalently linked protein on calicivirus RNA. J Gen Virol. 1978 Nov;41(2):443-6. PMID:569187
- ↑ Pfister T, Wimmer E. Polypeptide p41 of a Norwalk-like virus is a nucleic acid-independent nucleoside triphosphatase. J Virol. 2001 Feb;75(4):1611-9. PMID:11160659 doi:10.1128/JVI.75.4.1611-1619.2001
- ↑ Burroughs JN, Brown F. Presence of a covalently linked protein on calicivirus RNA. J Gen Virol. 1978 Nov;41(2):443-6. PMID:569187
- ↑ Pfister T, Wimmer E. Polypeptide p41 of a Norwalk-like virus is a nucleic acid-independent nucleoside triphosphatase. J Virol. 2001 Feb;75(4):1611-9. PMID:11160659 doi:10.1128/JVI.75.4.1611-1619.2001
- ↑ Burroughs JN, Brown F. Presence of a covalently linked protein on calicivirus RNA. J Gen Virol. 1978 Nov;41(2):443-6. PMID:569187
- ↑ Pfister T, Wimmer E. Polypeptide p41 of a Norwalk-like virus is a nucleic acid-independent nucleoside triphosphatase. J Virol. 2001 Feb;75(4):1611-9. PMID:11160659 doi:10.1128/JVI.75.4.1611-1619.2001
- ↑ Burroughs JN, Brown F. Presence of a covalently linked protein on calicivirus RNA. J Gen Virol. 1978 Nov;41(2):443-6. PMID:569187
- ↑ Pfister T, Wimmer E. Polypeptide p41 of a Norwalk-like virus is a nucleic acid-independent nucleoside triphosphatase. J Virol. 2001 Feb;75(4):1611-9. PMID:11160659 doi:10.1128/JVI.75.4.1611-1619.2001
- ↑ Galasiti Kankanamalage AC, Kim Y, Rathnayake AD, Damalanka VC, Weerawarna PM, Doyle ST, Alsoudi AF, Dissanayake DM, Lushington GH, Mehzabeen N, Battaile KP, Lovell S, Chang KO, Groutas WC. Structure-based exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design of potent and permeable inhibitors. Eur J Med Chem. 2016 Nov 14;126:502-516. doi: 10.1016/j.ejmech.2016.11.027. PMID:27914364 doi:http://dx.doi.org/10.1016/j.ejmech.2016.11.027
|
