6skb: Difference between revisions
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The | ==Crystal Structure of Human Kallikrein 6 (N217D/I218Y/K224R) in complex with GSK3496783A== | ||
<StructureSection load='6skb' size='340' side='right'caption='[[6skb]], [[Resolution|resolution]] 1.84Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6skb]] is a 3 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=6SKB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SKB FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.84Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=LH5:4-[(3~{S})-1-oxidanyl-3,4-dihydro-2,1-benzoxaborinin-3-yl]-2-(pyridin-3-ylmethoxy)benzenecarboximidamide'>LH5</scene>, <scene name='pdbligand=RH5:4-[(3~{R})-1-oxidanyl-3,4-dihydro-2,1-benzoxaborinin-3-yl]-2-(pyridin-3-ylmethoxy)benzenecarboximidamide'>RH5</scene></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=6skb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6skb OCA], [https://pdbe.org/6skb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6skb RCSB], [https://www.ebi.ac.uk/pdbsum/6skb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6skb ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[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;"> | |||
== Publication Abstract from PubMed == | |||
The connection between Netherton syndrome and overactivation of epidermal/dermal proteases, particularly Kallikrein 5 (KLK5) has been well established and it is expected that a KLK5 inhibitor would improve the dermal barrier and also reduce the pain and itch that afflict Netherton syndrome patients. One of the challenges of covalent protease inhibitors has been achieving selectivity over closely related targets. In this paper we describe the use of structural insight to design and develop a selective and highly potent reversibly covalent KLK5 inhibitor from an initial weakly binding fragment. | |||
Design and development of a series of borocycles as selective, covalent kallikrein 5 inhibitors.,Walker AL, Denis A, Bingham RP, Bouillot A, Edgar EV, Ferrie A, Holmes DS, Laroze A, Liddle J, Fouchet MH, Moquette A, Nassau P, Pearce AC, Polyakova O, Smith KJ, Thomas P, Thorpe JH, Trottet L, Wang Y, Hovnanian A Bioorg Med Chem Lett. 2019 Oct 15;29(20):126675. doi: 10.1016/j.bmcl.2019.126675. , Epub 2019 Sep 7. PMID:31521475<ref>PMID:31521475</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6skb" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Kallikrein 3D structures|Kallikrein 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Thorpe JH]] | |||
Latest revision as of 15:43, 24 January 2024
Crystal Structure of Human Kallikrein 6 (N217D/I218Y/K224R) in complex with GSK3496783ACrystal Structure of Human Kallikrein 6 (N217D/I218Y/K224R) in complex with GSK3496783A
Structural highlights
FunctionKLK6_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 PubMedThe connection between Netherton syndrome and overactivation of epidermal/dermal proteases, particularly Kallikrein 5 (KLK5) has been well established and it is expected that a KLK5 inhibitor would improve the dermal barrier and also reduce the pain and itch that afflict Netherton syndrome patients. One of the challenges of covalent protease inhibitors has been achieving selectivity over closely related targets. In this paper we describe the use of structural insight to design and develop a selective and highly potent reversibly covalent KLK5 inhibitor from an initial weakly binding fragment. Design and development of a series of borocycles as selective, covalent kallikrein 5 inhibitors.,Walker AL, Denis A, Bingham RP, Bouillot A, Edgar EV, Ferrie A, Holmes DS, Laroze A, Liddle J, Fouchet MH, Moquette A, Nassau P, Pearce AC, Polyakova O, Smith KJ, Thomas P, Thorpe JH, Trottet L, Wang Y, Hovnanian A Bioorg Med Chem Lett. 2019 Oct 15;29(20):126675. doi: 10.1016/j.bmcl.2019.126675. , Epub 2019 Sep 7. PMID:31521475[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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