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| | <StructureSection load='5o4v' size='340' side='right'caption='[[5o4v]], [[Resolution|resolution]] 1.70Å' scene=''> | | <StructureSection load='5o4v' size='340' side='right'caption='[[5o4v]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5o4v]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Haemamoeba_vivax Haemamoeba vivax]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5O4V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5O4V FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5o4v]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_vivax Plasmodium vivax]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5O4V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5O4V FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9K2:1-[5-(4-fluoranyl-2-methyl-phenyl)-1~{H}-indazol-3-yl]-~{N},~{N}-dimethyl-methanamine'>9K2</scene>, <scene name='pdbligand=9KZ:ethyl+2,4-dimethylquinoline-3-carboxylate'>9KZ</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NHW:2-OXOPENTADECYL-COA'>NHW</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.7Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5o48|5o48]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9K2:1-[5-(4-fluoranyl-2-methyl-phenyl)-1~{H}-indazol-3-yl]-~{N},~{N}-dimethyl-methanamine'>9K2</scene>, <scene name='pdbligand=9KZ:ethyl+2,4-dimethylquinoline-3-carboxylate'>9KZ</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NHW:2-OXOPENTADECYL-COA'>NHW</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PVX_085815 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5855 Haemamoeba vivax])</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=5o4v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5o4v OCA], [https://pdbe.org/5o4v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5o4v RCSB], [https://www.ebi.ac.uk/pdbsum/5o4v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5o4v ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glycylpeptide_N-tetradecanoyltransferase Glycylpeptide N-tetradecanoyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.97 2.3.1.97] </span></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=5o4v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5o4v OCA], [http://pdbe.org/5o4v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5o4v RCSB], [http://www.ebi.ac.uk/pdbsum/5o4v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5o4v ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/A5K1A2_PLAVS A5K1A2_PLAVS]] Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins (By similarity).[RuleBase:RU000586] | + | [https://www.uniprot.org/uniprot/A5K1A2_PLAVS A5K1A2_PLAVS] Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins (By similarity).[RuleBase:RU000586] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Glycylpeptide N-tetradecanoyltransferase]] | |
| - | [[Category: Haemamoeba vivax]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Brannigan, J A]] | + | [[Category: Plasmodium vivax]] |
| - | [[Category: Wilkinson, A J]] | + | [[Category: Brannigan JA]] |
| - | [[Category: Inhibitor]] | + | [[Category: Wilkinson AJ]] |
| - | [[Category: Myristoyl]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
5o4v is a 3 chain structure with sequence from Plasmodium vivax. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.7Å |
| Ligands: | , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
A5K1A2_PLAVS Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins (By similarity).[RuleBase:RU000586]
Publication Abstract from PubMed
Rhinoviruses (RVs) are the pathogens most often responsible for the common cold, and are a frequent cause of exacerbations in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we report the discovery of IMP-1088, a picomolar dual inhibitor of the human N-myristoyltransferases NMT1 and NMT2, and use it to demonstrate that pharmacological inhibition of host-cell N-myristoylation rapidly and completely prevents rhinoviral replication without inducing cytotoxicity. The identification of cooperative binding between weak-binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking and conformational control over linker geometry. We show that inhibition of the co-translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, to deliver a low nanomolar antiviral activity against multiple RV strains, poliovirus and foot and-mouth disease virus, and protection of cells against virus-induced killing, highlighting the potential of host myristoylation as a drug target in picornaviral infections.
Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus.,Mousnier A, Bell AS, Swieboda DP, Morales-Sanfrutos J, Perez-Dorado I, Brannigan JA, Newman J, Ritzefeld M, Hutton JA, Guedan A, Asfor AS, Robinson SW, Hopkins-Navratilova I, Wilkinson AJ, Johnston SL, Leatherbarrow RJ, Tuthill TJ, Solari R, Tate EW Nat Chem. 2018 May 14. pii: 10.1038/s41557-018-0039-2. doi:, 10.1038/s41557-018-0039-2. PMID:29760414[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mousnier A, Bell AS, Swieboda DP, Morales-Sanfrutos J, Perez-Dorado I, Brannigan JA, Newman J, Ritzefeld M, Hutton JA, Guedan A, Asfor AS, Robinson SW, Hopkins-Navratilova I, Wilkinson AJ, Johnston SL, Leatherbarrow RJ, Tuthill TJ, Solari R, Tate EW. Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus. Nat Chem. 2018 May 14. pii: 10.1038/s41557-018-0039-2. doi:, 10.1038/s41557-018-0039-2. PMID:29760414 doi:http://dx.doi.org/10.1038/s41557-018-0039-2
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