6f06: Difference between revisions
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==CATHEPSIN L IN COMPLEX WITH (3S,14E)-8-(azetidin-3-yl)-19-chloro-N-(1-cyanocyclopropyl)-5-oxo-12,17-dioxa-4-azatricyclo[16.2.2.06,11]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxamide== | |||
<StructureSection load='6f06' size='340' side='right' caption='[[6f06]], [[Resolution|resolution]] 2.02Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6f06]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F06 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6F06 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C7T:(3~{S},14~{E})-8-(azetidin-3-yl)-19-chloranyl-~{N}-(1-cyanocyclopropyl)-5-oxidanylidene-12,17-dioxa-4-azatricyclo[16.2.2.0^{6,11}]docosa-1(21),6(11),7,9,14,18(22),19-heptaene-3-carboxamide'>C7T</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6ezp|6ezp]], [[6ezx|6ezx]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cathepsin_L Cathepsin L], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.15 3.4.22.15] </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=6f06 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f06 OCA], [http://pdbe.org/6f06 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6f06 RCSB], [http://www.ebi.ac.uk/pdbsum/6f06 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6f06 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/CATL1_HUMAN CATL1_HUMAN]] Important for the overall degradation of proteins in lysosomes. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) -like cysteine protease produced by Trypanosoma brucei (T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors (Ki < 10 nM), preventing the cell-growth of T. b. rhodesiense (IC50 < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a non-covalent binding mode of this ligand class, due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys-SOH) during crystallization. The P-glycoprotein efflux ratio was measured and the in vivo brain penetration in rats determined. When tested in vivo in acute HAT model, the compounds permitted up to 16.25 (vs. 13.0 for untreated controls) mean days of survival. | |||
Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.,Giroud M, Dietzel U, Anselm L, Banner D, Kuglstatter A, Benz J, Blanc JB, Gaufreteau D, Liu H, Lin X, Stich A, Kuhn B, Schuler F, Kaiser M, Brun R, Schirmeister T, Kisker C, Diederich F, Haap W J Med Chem. 2018 Mar 29. doi: 10.1021/acs.jmedchem.7b01869. PMID:29590750<ref>PMID:29590750</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6f06" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Cathepsin L]] | |||
[[Category: Kuglstatter, A]] | [[Category: Kuglstatter, A]] | ||
[[Category: Stihle, M]] | [[Category: Stihle, M]] | ||
[[Category: Hydrolase]] | |||
[[Category: Hydrolase-hydrolase inhibitor complex]] | |||
[[Category: Protease inhibitor]] | |||
Latest revision as of 16:57, 11 April 2018
CATHEPSIN L IN COMPLEX WITH (3S,14E)-8-(azetidin-3-yl)-19-chloro-N-(1-cyanocyclopropyl)-5-oxo-12,17-dioxa-4-azatricyclo[16.2.2.06,11]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxamideCATHEPSIN L IN COMPLEX WITH (3S,14E)-8-(azetidin-3-yl)-19-chloro-N-(1-cyanocyclopropyl)-5-oxo-12,17-dioxa-4-azatricyclo[16.2.2.06,11]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxamide
Structural highlights
Function[CATL1_HUMAN] Important for the overall degradation of proteins in lysosomes. Publication Abstract from PubMedRhodesain (RD) is a parasitic, human cathepsin L (hCatL) -like cysteine protease produced by Trypanosoma brucei (T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors (Ki < 10 nM), preventing the cell-growth of T. b. rhodesiense (IC50 < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a non-covalent binding mode of this ligand class, due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys-SOH) during crystallization. The P-glycoprotein efflux ratio was measured and the in vivo brain penetration in rats determined. When tested in vivo in acute HAT model, the compounds permitted up to 16.25 (vs. 13.0 for untreated controls) mean days of survival. Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.,Giroud M, Dietzel U, Anselm L, Banner D, Kuglstatter A, Benz J, Blanc JB, Gaufreteau D, Liu H, Lin X, Stich A, Kuhn B, Schuler F, Kaiser M, Brun R, Schirmeister T, Kisker C, Diederich F, Haap W J Med Chem. 2018 Mar 29. doi: 10.1021/acs.jmedchem.7b01869. PMID:29590750[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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