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| | ==Kallikrein-related peptidase 8 leupeptin inhibitor complex== | | ==Kallikrein-related peptidase 8 leupeptin inhibitor complex== |
| - | <StructureSection load='5ms4' size='340' side='right' caption='[[5ms4]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='5ms4' size='340' side='right'caption='[[5ms4]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ms4]] is a 4 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=5MS4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MS4 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ms4]] is a 8 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=5MS4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MS4 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SVC:N-acetyl-L-leucyl-N-[(2S)-5-carbamimidamido-1-hydroxypentan-2-yl]-L-leucinamide'>SVC</scene>, <scene name='pdbligand=TBU:TERTIARY-BUTYL+ALCOHOL'>TBU</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]] 2.1Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KLK8, NRPN, PRSS19, TADG14, UNQ283/PRO322 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</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=PRD_000216:LEUPEPTIN'>PRD_000216</scene>, <scene name='pdbligand=TBU:TERTIARY-BUTYL+ALCOHOL'>TBU</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Kallikrein_8 Kallikrein 8], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.118 3.4.21.118] </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=5ms4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ms4 OCA], [https://pdbe.org/5ms4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ms4 RCSB], [https://www.ebi.ac.uk/pdbsum/5ms4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ms4 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=5ms4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ms4 OCA], [http://pdbe.org/5ms4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ms4 RCSB], [http://www.ebi.ac.uk/pdbsum/5ms4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ms4 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/KLK8_HUMAN KLK8_HUMAN]] Serine protease which is capable of degrading a number of proteins such as casein, fibrinogen, kininogen, fibronectin and collagen type IV. Also cleaves L1CAM in response to increased neural activity. Induces neurite outgrowth and fasciculation of cultured hippocampal neurons. Plays a role in the formation and maturation of orphan and small synaptic boutons in the Schaffer-collateral pathway, regulates Schaffer-collateral long-term potentiation in the hippocampus and is required for memory acquisition and synaptic plasticity. Involved in skin desquamation and keratinocyte proliferation. Plays a role in the secondary phase of pathogenesis following spinal cord injury.<ref>PMID:16337200</ref> | + | [https://www.uniprot.org/uniprot/KLK8_HUMAN KLK8_HUMAN] Serine protease which is capable of degrading a number of proteins such as casein, fibrinogen, kininogen, fibronectin and collagen type IV. Also cleaves L1CAM in response to increased neural activity. Induces neurite outgrowth and fasciculation of cultured hippocampal neurons. Plays a role in the formation and maturation of orphan and small synaptic boutons in the Schaffer-collateral pathway, regulates Schaffer-collateral long-term potentiation in the hippocampus and is required for memory acquisition and synaptic plasticity. Involved in skin desquamation and keratinocyte proliferation. Plays a role in the secondary phase of pathogenesis following spinal cord injury.<ref>PMID:16337200</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Kallikrein|Kallikrein]] | + | *[[Kallikrein 3D structures|Kallikrein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Kallikrein 8]] | + | [[Category: Large Structures]] |
| - | [[Category: Bode, W]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Brandstetter, H]] | + | [[Category: Bode W]] |
| - | [[Category: Debela, M]] | + | [[Category: Brandstetter H]] |
| - | [[Category: Goettig, P]] | + | [[Category: Debela M]] |
| - | [[Category: Magdolen, V]] | + | [[Category: Goettig P]] |
| - | [[Category: Skala, W]] | + | [[Category: Magdolen V]] |
| - | [[Category: Aldehyde inhibitor]]
| + | [[Category: Skala W]] |
| - | [[Category: Ca2+ complex]]
| + | |
| - | [[Category: Hydrolase-inhibitor complex]]
| + | |
| - | [[Category: Synaptic remodeling]]
| + | |
| - | [[Category: Trypsin-like serine protease]]
| + | |
| Structural highlights
5ms4 is a 8 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 2.1Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
KLK8_HUMAN Serine protease which is capable of degrading a number of proteins such as casein, fibrinogen, kininogen, fibronectin and collagen type IV. Also cleaves L1CAM in response to increased neural activity. Induces neurite outgrowth and fasciculation of cultured hippocampal neurons. Plays a role in the formation and maturation of orphan and small synaptic boutons in the Schaffer-collateral pathway, regulates Schaffer-collateral long-term potentiation in the hippocampus and is required for memory acquisition and synaptic plasticity. Involved in skin desquamation and keratinocyte proliferation. Plays a role in the secondary phase of pathogenesis following spinal cord injury.[1]
Publication Abstract from PubMed
Human KLK8/neuropsin, a kallikrein-related serine peptidase, is mostly expressed in skin and the hippocampus regions of the brain, where it regulates memory formation by synaptic remodeling. Substrate profiles of recombinant KLK8 were analyzed with positional scanning using fluorogenic tetrapeptides and the proteomic PICS approach, which revealed the prime side specificity. Enzyme kinetics with optimized substrates showed stimulation by Ca(2+) and inhibition by Zn(2+), which are physiological regulators. Crystal structures of KLK8 with a ligand-free active site and with the inhibitor leupeptin explain the subsite specificity and display Ca(2+) bound to the 75-loop. The variants D70K and H99A confirmed the antagonistic role of the cation binding sites. Molecular docking and dynamics calculations provided insights in substrate binding and the dual regulation of activity by Ca(2+) and Zn(2+), which are important in neuron and skin physiology. Both cations participate in the allosteric surface loop network present in related serine proteases. A comparison of the positional scanning data with substrates from brain suggests an adaptive recognition by KLK8, based on the tertiary structures of its targets. These combined findings provide a comprehensive picture of the molecular mechanisms underlying the enzyme activity of KLK8.
Structural determinants of specificity and regulation of activity in the allosteric loop network of human KLK8/neuropsin.,Debela M, Magdolen V, Skala W, Elsasser B, Schneider EL, Craik CS, Biniossek ML, Schilling O, Bode W, Brandstetter H, Goettig P Sci Rep. 2018 Jul 16;8(1):10705. doi: 10.1038/s41598-018-29058-6. PMID:30013126[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Rajapakse S, Ogiwara K, Takano N, Moriyama A, Takahashi T. Biochemical characterization of human kallikrein 8 and its possible involvement in the degradation of extracellular matrix proteins. FEBS Lett. 2005 Dec 19;579(30):6879-84. doi: 10.1016/j.febslet.2005.11.039. Epub , 2005 Dec 1. PMID:16337200 doi:http://dx.doi.org/10.1016/j.febslet.2005.11.039
- ↑ Debela M, Magdolen V, Skala W, Elsasser B, Schneider EL, Craik CS, Biniossek ML, Schilling O, Bode W, Brandstetter H, Goettig P. Structural determinants of specificity and regulation of activity in the allosteric loop network of human KLK8/neuropsin. Sci Rep. 2018 Jul 16;8(1):10705. doi: 10.1038/s41598-018-29058-6. PMID:30013126 doi:http://dx.doi.org/10.1038/s41598-018-29058-6
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