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| | ==Mouse kallikrein 7 in complex with 6-benzyl-1,4-diazepan-7-one derivative== | | ==Mouse kallikrein 7 in complex with 6-benzyl-1,4-diazepan-7-one derivative== |
| - | <StructureSection load='5zfi' size='340' side='right' caption='[[5zfi]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='5zfi' size='340' side='right'caption='[[5zfi]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5zfi]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZFI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ZFI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5zfi]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZFI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ZFI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9C9:2-[(3Z,6R)-6-[(2,6-dichlorophenyl)methyl]-3-(dimethylhydrazinylidene)-7-oxo-1,4-diazepan-1-yl]-N-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]acetamide'>9C9</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</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]] 1.8Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5zfh|5zfh]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9C9:2-[(3Z,6R)-6-[(2,6-dichlorophenyl)methyl]-3-(dimethylhydrazinylidene)-7-oxo-1,4-diazepan-1-yl]-N-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]acetamide'>9C9</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Klk7, Prss6, Scce ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</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=5zfi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zfi OCA], [https://pdbe.org/5zfi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5zfi RCSB], [https://www.ebi.ac.uk/pdbsum/5zfi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5zfi 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/Stratum_corneum_chymotryptic_enzyme Stratum corneum chymotryptic enzyme], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.117 3.4.21.117] </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=5zfi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zfi OCA], [http://pdbe.org/5zfi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zfi RCSB], [http://www.ebi.ac.uk/pdbsum/5zfi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zfi ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/KLK7_MOUSE KLK7_MOUSE]] May catalyze the degradation of intercellular cohesive structures in the cornified layer of the skin in the continuous shedding of cells from the skin surface. Specific for amino acid residues with aromatic side chains in the P1 position. Cleaves insulin A chain at '14-Tyr-|-Gln-15' and insulin B chain at '6-Leu-|-Cys-7', '16-Tyr-|-Leu-17', '25-Phe-|-Tyr-26' and '26-Tyr-|-Thr-27'. Could play a role in the activation of precursors to inflammatory cytokines. | + | [https://www.uniprot.org/uniprot/KLK7_MOUSE KLK7_MOUSE] May catalyze the degradation of intercellular cohesive structures in the cornified layer of the skin in the continuous shedding of cells from the skin surface. Specific for amino acid residues with aromatic side chains in the P1 position. Cleaves insulin A chain at '14-Tyr-|-Gln-15' and insulin B chain at '6-Leu-|-Cys-7', '16-Tyr-|-Leu-17', '25-Phe-|-Tyr-26' and '26-Tyr-|-Thr-27'. Could play a role in the activation of precursors to inflammatory cytokines. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5zfi" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5zfi" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Kallikrein 3D structures|Kallikrein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Large Structures]] |
| - | [[Category: Stratum corneum chymotryptic enzyme]] | + | [[Category: Mus musculus]] |
| - | [[Category: Sugawara, H]] | + | [[Category: Sugawara H]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Inhibitor complex]]
| + | |
| - | [[Category: Protease]]
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| Structural highlights
Function
KLK7_MOUSE May catalyze the degradation of intercellular cohesive structures in the cornified layer of the skin in the continuous shedding of cells from the skin surface. Specific for amino acid residues with aromatic side chains in the P1 position. Cleaves insulin A chain at '14-Tyr-|-Gln-15' and insulin B chain at '6-Leu-|-Cys-7', '16-Tyr-|-Leu-17', '25-Phe-|-Tyr-26' and '26-Tyr-|-Thr-27'. Could play a role in the activation of precursors to inflammatory cytokines.
Publication Abstract from PubMed
A series of 1,3,6-trisubstituted 1,4-diazepan-7-ones were prepared as kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Previously reported compounds 1-3 were potent human KLK7 inhibitors; however, they did not exhibit inhibitory activity against mouse KLK7. Comparison of the human and mouse KLK7 structures reveals the cause of this species differences; therefore, compounds that could inhibit both KLK7s were designed, synthesized, and evaluated. Through this structure-based drug design, compound 22g was identified as an inhibitor against human and mouse KLK7, and only one of the enantiomers, (-)-22g, exhibited potent inhibitory activity. Furthermore, the crystal structure of mouse KLK7 complexed with 22g enabled the elucidation of structure-activity relationships and justified 22g as a valuable compound to overcome the species differences.
Structure-based drug design to overcome species differences in kallikrein 7 inhibition of 1,3,6-trisubstituted 1,4-diazepan-7-ones.,Murafuji H, Sugawara H, Goto M, Oyama Y, Sakai H, Imajo S, Tomoo T, Muto T Bioorg Med Chem. 2018 Jul 23;26(12):3639-3653. doi: 10.1016/j.bmc.2018.05.044., Epub 2018 May 26. PMID:29884582[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Murafuji H, Sugawara H, Goto M, Oyama Y, Sakai H, Imajo S, Tomoo T, Muto T. Structure-based drug design to overcome species differences in kallikrein 7 inhibition of 1,3,6-trisubstituted 1,4-diazepan-7-ones. Bioorg Med Chem. 2018 Jul 23;26(12):3639-3653. doi: 10.1016/j.bmc.2018.05.044., Epub 2018 May 26. PMID:29884582 doi:http://dx.doi.org/10.1016/j.bmc.2018.05.044
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