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| | ==Crystal structure of HPK1 kinase domain S171A mutant== | | ==Crystal structure of HPK1 kinase domain S171A mutant== |
| - | <StructureSection load='6cqe' size='340' side='right' caption='[[6cqe]], [[Resolution|resolution]] 1.89Å' scene=''> | + | <StructureSection load='6cqe' size='340' side='right'caption='[[6cqe]], [[Resolution|resolution]] 1.89Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6cqe]] is a 2 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=6CQE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CQE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6cqe]] is a 2 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=6CQE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CQE FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAP4K1, HPK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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]] 1.886Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=6cqe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cqe OCA], [https://pdbe.org/6cqe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cqe RCSB], [https://www.ebi.ac.uk/pdbsum/6cqe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cqe ProSAT]</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=6cqe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cqe OCA], [http://pdbe.org/6cqe PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cqe RCSB], [http://www.ebi.ac.uk/pdbsum/6cqe PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cqe ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/M4K1_HUMAN M4K1_HUMAN]] Serine/threonine-protein kinase, which may play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway. May play a role in hematopoietic lineage decisions and growth regulation. Able to autophosphorylate.<ref>PMID:24362026</ref> <ref>PMID:8824585</ref> | + | [https://www.uniprot.org/uniprot/M4K1_HUMAN M4K1_HUMAN] Serine/threonine-protein kinase, which may play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway. May play a role in hematopoietic lineage decisions and growth regulation. Able to autophosphorylate.<ref>PMID:24362026</ref> <ref>PMID:8824585</ref> |
| - | <div style="background-color:#fffaf0;">
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| - | == Publication Abstract from PubMed ==
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| - | Enhancement of antigen-specific T cell immunity has shown significant therapeutic benefit in infectious diseases and cancer. Hematopoietic progenitor kinase-1 (HPK1) is a negative-feedback regulator of T cell receptor signaling, which dampens T cell proliferation and effector function. A recent report showed that a catalytic dead mutant of HPK1 phenocopies augmented T cell responses observed in HPK1-knockout mice, indicating that kinase activity is critical for function. We evaluated active and inactive mutants and determined crystal structures of HPK1 kinase domain (HPK1-KD) in apo and ligand bound forms. In all structures HPK1-KD displays a rare domain-swapped dimer, in which the activation segment comprises a well-conserved dimer interface. Biophysical measurements show formation of dimer in solution. The activation segment adopts an alpha-helical structure which exhibits distinct orientations in active and inactive states. This face-to-face configuration suggests that the domain-swapped dimer may possess alternative selectivity for certain substrates of HPK1 under relevant cellular context.
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| - | Hematopoietic Progenitor Kinase-1 Structure in a Domain-Swapped Dimer.,Wu P, Sneeringer CJ, Pitts KE, Day ES, Chan BK, Wei B, Lehoux I, Mortara K, Li H, Wu J, Franke Y, Moffat JG, Grogan JL, Heffron TP, Wang W Structure. 2018 Nov 13. pii: S0969-2126(18)30386-1. doi:, 10.1016/j.str.2018.10.025. PMID:30503777<ref>PMID:30503777</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 6cqe" style="background-color:#fffaf0;"></div>
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| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Non-specific serine/threonine protein kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Franke, Y]] | + | [[Category: Franke Y]] |
| - | [[Category: Lehoux, I]] | + | [[Category: Lehoux I]] |
| - | [[Category: Mortara, K]] | + | [[Category: Mortara K]] |
| - | [[Category: Wang, W]] | + | [[Category: Wang W]] |
| - | [[Category: Wu, P]] | + | [[Category: Wu P]] |
| - | [[Category: Protein kinase]]
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| - | [[Category: Transferase]]
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