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| | <StructureSection load='6kd5' size='340' side='right'caption='[[6kd5]], [[Resolution|resolution]] 2.60Å' scene=''> | | <StructureSection load='6kd5' size='340' side='right'caption='[[6kd5]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6kd5]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KD5 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6KD5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6kd5]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KD5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6KD5 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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]] 2.6Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=0QE:CHLOROMETHANE'>0QE</scene>, <scene name='pdbligand=AR7:AMINO{[(4S)-4-AMINO-5,5-DIHYDROXYPENTYL]AMINO}METHANIMINIUM'>AR7</scene>, <scene name='pdbligand=DKA:DECANOIC+ACID'>DKA</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0QE:CHLOROMETHANE'>0QE</scene>, <scene name='pdbligand=AR7:AMINO{[(4S)-4-AMINO-5,5-DIHYDROXYPENTYL]AMINO}METHANIMINIUM'>AR7</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=DKA:DECANOIC+ACID'>DKA</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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">TMPRSS13, MSP, TMPRSS11 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6kd5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kd5 OCA], [https://pdbe.org/6kd5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6kd5 RCSB], [https://www.ebi.ac.uk/pdbsum/6kd5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6kd5 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6kd5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kd5 OCA], [http://pdbe.org/6kd5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6kd5 RCSB], [http://www.ebi.ac.uk/pdbsum/6kd5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6kd5 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/TMPSD_HUMAN TMPSD_HUMAN] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| - | Approaches to increase the activity of chimeric antigen receptor (CAR)-T cells against solid tumors may also increase the risk of toxicity and other side effects. To improve the safety of CAR-T-cell therapy, we computationally designed a chemically disruptable heterodimer (CDH) based on the binding of two human proteins. The CDH self-assembles, can be disrupted by a small-molecule drug and has a high-affinity protein interface with minimal amino acid deviation from wild-type human proteins. We incorporated the CDH into a synthetic heterodimeric CAR, called STOP-CAR, that has an antigen-recognition chain and a CD3zeta- and CD28-containing endodomain signaling chain. We tested STOP-CAR-T cells specific for two antigens in vitro and in vivo and found similar antitumor activity compared to second-generation (2G) CAR-T cells. Timed administration of the small-molecule drug dynamically inactivated the activity of STOP-CAR-T cells. Our work highlights the potential for structure-based design to add controllable elements to synthetic cellular therapies.
| + | Infection of certain influenza viruses is triggered when its HA is cleaved by host cell proteases such as proprotein convertases and type II transmembrane serine proteases (TTSP). HA with a monobasic motif is cleaved by trypsin-like proteases, including TMPRSS2 and HAT, whereas the multibasic motif found in high pathogenicity avian influenza HA is cleaved by furin, PC5/6, or MSPL. MSPL belongs to the TMPRSS family and preferentially cleaves [R/K]-K-K-R downward arrow sequences. Here, we solved the crystal structure of the extracellular region of human MSPL in complex with an irreversible substrate-analog inhibitor. The structure revealed three domains clustered around the C-terminal alpha-helix of the SPD. The inhibitor structure and its putative model show that the P1-Arg inserts into the S1 pocket, whereas the P2-Lys and P4-Arg interacts with the Asp/Glu-rich 99-loop that is unique to MSPL. Based on the structure of MSPL, we also constructed a homology model of TMPRSS2, which is essential for the activation of the SARS-CoV-2 spike protein and infection. The model may provide the structural insight for the drug development for COVID-19. |
| | | | |
| - | A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy.,Giordano-Attianese G, Gainza P, Gray-Gaillard E, Cribioli E, Shui S, Kim S, Kwak MJ, Vollers S, Corria Osorio AJ, Reichenbach P, Bonet J, Oh BH, Irving M, Coukos G, Correia BE Nat Biotechnol. 2020 Apr;38(4):426-432. doi: 10.1038/s41587-019-0403-9. Epub 2020, Feb 3. PMID:32015549<ref>PMID:32015549</ref>
| + | Crystal structure of inhibitor-bound human MSPL that can activate high pathogenic avian influenza.,Ohno A, Maita N, Tabata T, Nagano H, Arita K, Ariyoshi M, Uchida T, Nakao R, Ulla A, Sugiura K, Kishimoto K, Teshima-Kondo S, Okumura Y, Nikawa T Life Sci Alliance. 2021 Apr 5;4(6). pii: 4/6/e202000849. doi:, 10.26508/lsa.202000849. Print 2021 Jun. PMID:33820827<ref>PMID:33820827</ref> |
| | | | |
| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | <div class="pdbe-citations 6kd5" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6kd5" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Transmembrane protease serine 2|Transmembrane protease serine 2]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Maita, N]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Nikawa, T]] | + | [[Category: Maita N]] |
| - | [[Category: Ohno, A]] | + | [[Category: Nikawa T]] |
| - | [[Category: Okumura, Y]] | + | [[Category: Ohno A]] |
| - | [[Category: Hydrolase]]
| + | [[Category: Okumura Y]] |
| - | [[Category: Structural protein-inhibitor complex]]
| + | |
| Structural highlights
6kd5 is a 3 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.6Å |
| Ligands: | , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
TMPSD_HUMAN
Publication Abstract from PubMed
Infection of certain influenza viruses is triggered when its HA is cleaved by host cell proteases such as proprotein convertases and type II transmembrane serine proteases (TTSP). HA with a monobasic motif is cleaved by trypsin-like proteases, including TMPRSS2 and HAT, whereas the multibasic motif found in high pathogenicity avian influenza HA is cleaved by furin, PC5/6, or MSPL. MSPL belongs to the TMPRSS family and preferentially cleaves [R/K]-K-K-R downward arrow sequences. Here, we solved the crystal structure of the extracellular region of human MSPL in complex with an irreversible substrate-analog inhibitor. The structure revealed three domains clustered around the C-terminal alpha-helix of the SPD. The inhibitor structure and its putative model show that the P1-Arg inserts into the S1 pocket, whereas the P2-Lys and P4-Arg interacts with the Asp/Glu-rich 99-loop that is unique to MSPL. Based on the structure of MSPL, we also constructed a homology model of TMPRSS2, which is essential for the activation of the SARS-CoV-2 spike protein and infection. The model may provide the structural insight for the drug development for COVID-19.
Crystal structure of inhibitor-bound human MSPL that can activate high pathogenic avian influenza.,Ohno A, Maita N, Tabata T, Nagano H, Arita K, Ariyoshi M, Uchida T, Nakao R, Ulla A, Sugiura K, Kishimoto K, Teshima-Kondo S, Okumura Y, Nikawa T Life Sci Alliance. 2021 Apr 5;4(6). pii: 4/6/e202000849. doi:, 10.26508/lsa.202000849. Print 2021 Jun. PMID:33820827[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ohno A, Maita N, Tabata T, Nagano H, Arita K, Ariyoshi M, Uchida T, Nakao R, Ulla A, Sugiura K, Kishimoto K, Teshima-Kondo S, Okumura Y, Nikawa T. Crystal structure of inhibitor-bound human MSPL that can activate high pathogenic avian influenza. Life Sci Alliance. 2021 Apr 5;4(6). pii: 4/6/e202000849. doi:, 10.26508/lsa.202000849. Print 2021 Jun. PMID:33820827 doi:http://dx.doi.org/10.26508/lsa.202000849
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