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| | ==Virtual Screening and X-Ray Crystallography for Human Kallikrein 6 Inhibitors with an Amidinothiophene P1 Group== | | ==Virtual Screening and X-Ray Crystallography for Human Kallikrein 6 Inhibitors with an Amidinothiophene P1 Group== |
| - | <StructureSection load='3vfe' size='340' side='right' caption='[[3vfe]], [[Resolution|resolution]] 1.88Å' scene=''> | + | <StructureSection load='3vfe' size='340' side='right'caption='[[3vfe]], [[Resolution|resolution]] 1.88Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3vfe]] is a 1 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=3VFE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3VFE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3vfe]] 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=3VFE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3VFE FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0HL:4-{[(3R)-3-{[(7-METHOXYNAPHTHALEN-2-YL)SULFONYL](THIOPHEN-3-YLMETHYL)AMINO}-2-OXOPYRROLIDIN-1-YL]METHYL}THIOPHENE-2-CARBOXIMIDAMIDE'>0HL</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]] 1.88Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KLK6, PRSS18, PRSS9 ([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=0HL:4-{[(3R)-3-{[(7-METHOXYNAPHTHALEN-2-YL)SULFONYL](THIOPHEN-3-YLMETHYL)AMINO}-2-OXOPYRROLIDIN-1-YL]METHYL}THIOPHENE-2-CARBOXIMIDAMIDE'>0HL</scene></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=3vfe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3vfe OCA], [http://pdbe.org/3vfe PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3vfe RCSB], [http://www.ebi.ac.uk/pdbsum/3vfe PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3vfe 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=3vfe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3vfe OCA], [https://pdbe.org/3vfe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3vfe RCSB], [https://www.ebi.ac.uk/pdbsum/3vfe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3vfe ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/KLK6_HUMAN KLK6_HUMAN]] Serine protease which exhibits a preference for Arg over Lys in the substrate P1 position and for Ser or Pro in the P2 position. Shows activity against amyloid precursor protein, myelin basic protein, gelatin, casein and extracellular matrix proteins such as fibronectin, laminin, vitronectin and collagen. Degrades alpha-synuclein and prevents its polymerization, indicating that it may be involved in the pathogenesis of Parkinson disease and other synucleinopathies. May be involved in regulation of axon outgrowth following spinal cord injury. Tumor cells treated with a neutralizing KLK6 antibody migrate less than control cells, suggesting a role in invasion and metastasis.<ref>PMID:12878203</ref> <ref>PMID:12928483</ref> <ref>PMID:15557757</ref> <ref>PMID:16987227</ref> <ref>PMID:16321973</ref> <ref>PMID:11983703</ref> | + | [https://www.uniprot.org/uniprot/KLK6_HUMAN KLK6_HUMAN] Serine protease which exhibits a preference for Arg over Lys in the substrate P1 position and for Ser or Pro in the P2 position. Shows activity against amyloid precursor protein, myelin basic protein, gelatin, casein and extracellular matrix proteins such as fibronectin, laminin, vitronectin and collagen. Degrades alpha-synuclein and prevents its polymerization, indicating that it may be involved in the pathogenesis of Parkinson disease and other synucleinopathies. May be involved in regulation of axon outgrowth following spinal cord injury. Tumor cells treated with a neutralizing KLK6 antibody migrate less than control cells, suggesting a role in invasion and metastasis.<ref>PMID:12878203</ref> <ref>PMID:12928483</ref> <ref>PMID:15557757</ref> <ref>PMID:16987227</ref> <ref>PMID:16321973</ref> <ref>PMID:11983703</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| - | A series of hK6 inhibitors with a para-amidobenzylamine P1 group and a 2-hydroxybenzamide scaffold linker was discovered through virtual screening. The X-ray structure of hK6 complexed with compound 9b was determined to a resolution of 1.68A. The tertiary folding of the hK6 complexed with the inhibitor is conserved relative to the structure of the apo-protein, whereas the interaction between hK6 and the inhibitor is consistent with both the SAR and the in silico model used in the virtual screening. | + | A series of compounds with an amidinothiophene P1 group and a pyrrolidinone-sulphonamide scaffold linker was identified as potent inhibitors of human kallikrein 6 by structure-based virtual screening based on the union accessible binding space of serine proteases. As the first series of potent nonmechanism-based hK6 inhibitors, they may be used as tool compounds for target validation. An X-ray structure of a representative compound complexed with hK6, resolved at a resolution of 1.88 A, revealed that the amidinothiophene moiety bound in the S1 pocket and the pyrrolidinone-sulphonamide linker projected the aromatic tail into the S' pocket. |
| | | | |
| - | Human kallikrein 6 inhibitors with a para-amidobenzylanmine P1 group identified through virtual screening.,Liang G, Chen X, Aldous S, Pu SF, Mehdi S, Powers E, Xia T, Wang R Bioorg Med Chem Lett. 2012 Apr 1;22(7):2450-5. Epub 2012 Feb 14. PMID:22386244<ref>PMID:22386244</ref> | + | Virtual Screening and X-ray Crystallography for Human Kallikrein 6 Inhibitors with an Amidinothiophene P1 Group.,Liang G, Chen X, Aldous S, Pu SF, Mehdi S, Powers E, Giovanni A, Kongsamut S, Xia T, Zhang Y, Wang R, Gao Z, Merriman G, McLean LR, Morize I ACS Med Chem Lett. 2012 Jan 11;3(2):159-64. doi: 10.1021/ml200291e. eCollection , 2012 Feb 9. PMID:24900446<ref>PMID:24900446</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 3vfe" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 3vfe" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Kallikrein 3D structures|Kallikrein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Chen, X]] | + | [[Category: Large Structures]] |
| - | [[Category: Wang, R]] | + | [[Category: Chen X]] |
| - | [[Category: Xia, T]] | + | [[Category: Wang R]] |
| - | [[Category: Zhang, Y]] | + | [[Category: Xia T]] |
| - | [[Category: Amidinothiophene]]
| + | [[Category: Zhang Y]] |
| - | [[Category: Hk6]]
| + | |
| - | [[Category: Human kallikrein 6]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Protein-ligand complex]]
| + | |
| - | [[Category: Serine protease]]
| + | |
| Structural highlights
Function
KLK6_HUMAN Serine protease which exhibits a preference for Arg over Lys in the substrate P1 position and for Ser or Pro in the P2 position. Shows activity against amyloid precursor protein, myelin basic protein, gelatin, casein and extracellular matrix proteins such as fibronectin, laminin, vitronectin and collagen. Degrades alpha-synuclein and prevents its polymerization, indicating that it may be involved in the pathogenesis of Parkinson disease and other synucleinopathies. May be involved in regulation of axon outgrowth following spinal cord injury. Tumor cells treated with a neutralizing KLK6 antibody migrate less than control cells, suggesting a role in invasion and metastasis.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
A series of compounds with an amidinothiophene P1 group and a pyrrolidinone-sulphonamide scaffold linker was identified as potent inhibitors of human kallikrein 6 by structure-based virtual screening based on the union accessible binding space of serine proteases. As the first series of potent nonmechanism-based hK6 inhibitors, they may be used as tool compounds for target validation. An X-ray structure of a representative compound complexed with hK6, resolved at a resolution of 1.88 A, revealed that the amidinothiophene moiety bound in the S1 pocket and the pyrrolidinone-sulphonamide linker projected the aromatic tail into the S' pocket.
Virtual Screening and X-ray Crystallography for Human Kallikrein 6 Inhibitors with an Amidinothiophene P1 Group.,Liang G, Chen X, Aldous S, Pu SF, Mehdi S, Powers E, Giovanni A, Kongsamut S, Xia T, Zhang Y, Wang R, Gao Z, Merriman G, McLean LR, Morize I ACS Med Chem Lett. 2012 Jan 11;3(2):159-64. doi: 10.1021/ml200291e. eCollection , 2012 Feb 9. PMID:24900446[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Magklara A, Mellati AA, Wasney GA, Little SP, Sotiropoulou G, Becker GW, Diamandis EP. Characterization of the enzymatic activity of human kallikrein 6: Autoactivation, substrate specificity, and regulation by inhibitors. Biochem Biophys Res Commun. 2003 Aug 8;307(4):948-55. PMID:12878203
- ↑ Iwata A, Maruyama M, Akagi T, Hashikawa T, Kanazawa I, Tsuji S, Nukina N. Alpha-synuclein degradation by serine protease neurosin: implication for pathogenesis of synucleinopathies. Hum Mol Genet. 2003 Oct 15;12(20):2625-35. Epub 2003 Aug 19. PMID:12928483 doi:http://dx.doi.org/10.1093/hmg/ddg283
- ↑ Ghosh MC, Grass L, Soosaipillai A, Sotiropoulou G, Diamandis EP. Human kallikrein 6 degrades extracellular matrix proteins and may enhance the metastatic potential of tumour cells. Tumour Biol. 2004 Jul-Aug;25(4):193-9. PMID:15557757 doi:http://dx.doi.org/10.1159/000081102
- ↑ Scarisbrick IA, Sabharwal P, Cruz H, Larsen N, Vandell AG, Blaber SI, Ameenuddin S, Papke LM, Fehlings MG, Reeves RK, Blaber M, Windebank AJ, Rodriguez M. Dynamic role of kallikrein 6 in traumatic spinal cord injury. Eur J Neurosci. 2006 Sep;24(5):1457-69. PMID:16987227 doi:http://dx.doi.org/10.1111/j.1460-9568.2006.05021.x
- ↑ Angelo PF, Lima AR, Alves FM, Blaber SI, Scarisbrick IA, Blaber M, Juliano L, Juliano MA. Substrate specificity of human kallikrein 6: salt and glycosaminoglycan activation effects. J Biol Chem. 2006 Feb 10;281(6):3116-26. Epub 2005 Dec 1. PMID:16321973 doi:http://dx.doi.org/M510096200
- ↑ Bernett MJ, Blaber SI, Scarisbrick IA, Dhanarajan P, Thompson SM, Blaber M. Crystal structure and biochemical characterization of human kallikrein 6 reveals that a trypsin-like kallikrein is expressed in the central nervous system. J Biol Chem. 2002 Jul 5;277(27):24562-70. Epub 2002 Apr 30. PMID:11983703 doi:10.1074/jbc.M202392200
- ↑ Liang G, Chen X, Aldous S, Pu SF, Mehdi S, Powers E, Giovanni A, Kongsamut S, Xia T, Zhang Y, Wang R, Gao Z, Merriman G, McLean LR, Morize I. Virtual Screening and X-ray Crystallography for Human Kallikrein 6 Inhibitors with an Amidinothiophene P1 Group. ACS Med Chem Lett. 2012 Jan 11;3(2):159-64. PMID:24900446 doi:10.1021/ml200291e
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