7meq

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<StructureSection load='7meq' size='340' side='right'caption='[[7meq]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
<StructureSection load='7meq' size='340' side='right'caption='[[7meq]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[7meq]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MEQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MEQ FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7meq]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MEQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MEQ FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GBS:4-GUANIDINOBENZOIC+ACID'>GBS</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GBS:4-GUANIDINOBENZOIC+ACID'>GBS</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TMPRSS2, PRSS10 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7meq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7meq OCA], [https://pdbe.org/7meq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7meq RCSB], [https://www.ebi.ac.uk/pdbsum/7meq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7meq 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=7meq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7meq OCA], [https://pdbe.org/7meq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7meq RCSB], [https://www.ebi.ac.uk/pdbsum/7meq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7meq ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[https://www.uniprot.org/uniprot/TMPS2_HUMAN TMPS2_HUMAN]] Plasma membrane-anchored serine protease that participates in proteolytic cascades of relevance for the normal physiologic function of the prostate (PubMed:25122198). Androgen-induced TMPRSS2 activates several substrates that include pro-hepatocyte growth factor/HGF, the protease activated receptor-2/F2RL1 or matriptase/ST14 leading to extracellular matrix disruption and metastasis of prostate cancer cells (PubMed:15537383, PubMed:26018085, PubMed:25122198). In addition, activates trigeminal neurons and contribute to both spontaneous pain and mechanical allodynia (By similarity).[UniProtKB:Q9JIQ8]<ref>PMID:15537383</ref> <ref>PMID:25122198</ref> <ref>PMID:26018085</ref> (Microbial infection) Facilitates human coronaviruses SARS-CoV and SARS-CoV-2 infections via two independent mechanisms, proteolytic cleavage of ACE2 receptor which promotes viral uptake, and cleavage of coronavirus spike glycoproteins which activates the glycoprotein for host cell entry (PubMed:24227843, PubMed:32142651, PubMed:32404436). Proteolytically cleaves and activates the spike glycoproteins of human coronavirus 229E (HCoV-229E) and human coronavirus EMC (HCoV-EMC) and the fusion glycoproteins F0 of Sendai virus (SeV), human metapneumovirus (HMPV), human parainfluenza 1, 2, 3, 4a and 4b viruses (HPIV). Essential for spread and pathogenesis of influenza A virus (strains H1N1, H3N2 and H7N9); involved in proteolytic cleavage and activation of hemagglutinin (HA) protein which is essential for viral infectivity.<ref>PMID:21068237</ref> <ref>PMID:21325420</ref> <ref>PMID:23536651</ref> <ref>PMID:23966399</ref> <ref>PMID:24027332</ref> <ref>PMID:24227843</ref> <ref>PMID:32142651</ref> <ref>PMID:32404436</ref>
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[[https://www.uniprot.org/uniprot/TMPS2_HUMAN TMPS2_HUMAN]] Plasma membrane-anchored serine protease that participates in proteolytic cascades of relevance for the normal physiologic function of the prostate (PubMed:25122198). Androgen-induced TMPRSS2 activates several substrates that include pro-hepatocyte growth factor/HGF, the protease activated receptor-2/F2RL1 or matriptase/ST14 leading to extracellular matrix disruption and metastasis of prostate cancer cells (PubMed:15537383, PubMed:26018085, PubMed:25122198). In addition, activates trigeminal neurons and contribute to both spontaneous pain and mechanical allodynia (By similarity).[UniProtKB:Q9JIQ8]<ref>PMID:15537383</ref> <ref>PMID:25122198</ref> <ref>PMID:26018085</ref> (Microbial infection) Facilitates human coronaviruses SARS-CoV and SARS-CoV-2 infections via two independent mechanisms, proteolytic cleavage of ACE2 receptor which promotes viral uptake, and cleavage of coronavirus spike glycoproteins which activates the glycoprotein for host cell entry (PubMed:24227843, PubMed:32142651, PubMed:32404436). Proteolytically cleaves and activates the spike glycoproteins of human coronavirus 229E (HCoV-229E) and human coronavirus EMC (HCoV-EMC) and the fusion glycoproteins F0 of Sendai virus (SeV), human metapneumovirus (HMPV), human parainfluenza 1, 2, 3, 4a and 4b viruses (HPIV). Essential for spread and pathogenesis of influenza A virus (strains H1N1, H3N2 and H7N9); involved in proteolytic cleavage and activation of hemagglutinin (HA) protein which is essential for viral infectivity.<ref>PMID:21068237</ref> <ref>PMID:21325420</ref> <ref>PMID:23536651</ref> <ref>PMID:23966399</ref> <ref>PMID:24027332</ref> <ref>PMID:24227843</ref> <ref>PMID:32142651</ref> <ref>PMID:32404436</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Transmembrane protease, serine 2 (TMPRSS2) has been identified as key host cell factor for viral entry and pathogenesis of SARS-CoV-2. Specifically, TMPRSS2 proteolytically processes the SARS-CoV-2 Spike (S) protein, enabling virus-host membrane fusion and infection of the airways. We present here a recombinant production strategy for enzymatically active TMPRSS2 and characterization of its matured proteolytic activity, as well as its 1.95 A X-ray cocrystal structure with the synthetic protease inhibitor nafamostat. Our study provides a structural basis for the potent but nonspecific inhibition by nafamostat and identifies distinguishing features of the TMPRSS2 substrate binding pocket that explain specificity. TMPRSS2 cleaved SARS-CoV-2 S protein at multiple sites, including the canonical S1/S2 cleavage site. We ranked the potency of clinical protease inhibitors with half-maximal inhibitory concentrations ranging from 1.4 nM to 120 microM and determined inhibitor mechanisms of action, providing the groundwork for drug development efforts to selectively inhibit TMPRSS2.
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Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation.,Fraser BJ, Beldar S, Seitova A, Hutchinson A, Mannar D, Li Y, Kwon D, Tan R, Wilson RP, Leopold K, Subramaniam S, Halabelian L, Arrowsmith CH, Benard F Nat Chem Biol. 2022 Jun 8. pii: 10.1038/s41589-022-01059-7. doi:, 10.1038/s41589-022-01059-7. PMID:35676539<ref>PMID:35676539</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7meq" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Arrowsmith, C H]]
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[[Category: Arrowsmith CH]]
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[[Category: Beldar, S]]
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[[Category: Beldar S]]
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[[Category: Benard, F]]
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[[Category: Benard F]]
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[[Category: Edwards, A M]]
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[[Category: Edwards AM]]
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[[Category: Fraser, B]]
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[[Category: Fraser B]]
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[[Category: Halabelian, L]]
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[[Category: Halabelian L]]
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[[Category: Hutchinson, A]]
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[[Category: Hutchinson A]]
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[[Category: Li, Y]]
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[[Category: Li Y]]
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[[Category: Structural genomic]]
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[[Category: Seitova A]]
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[[Category: Seitova, A]]
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[[Category: Covid19]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Protease]]
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Revision as of 16:46, 7 September 2022

Crystal structure of human TMPRSS2 in complex with Nafamostat

PDB ID 7meq

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