View source for 6exq


==Crystal Structure of Rhodesain in complex with a Macrolactam Inhibitor==
<StructureSection load='6exq' size='340' side='right'caption='[[6exq]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6exq]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei_rhodesiense Trypanosoma brucei rhodesiense]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EXQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EXQ 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]] 2.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C2W:(3~{S})-19-chloranyl-~{N}-(1-cyanocyclopropyl)-8-methoxy-5-oxidanylidene-12,17-dioxa-4-azatricyclo[16.2.2.0^{6,11}]docosa-1(20),6(11),7,9,18,21-hexaene-3-carboxamide'>C2W</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=6exq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6exq OCA], [https://pdbe.org/6exq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6exq RCSB], [https://www.ebi.ac.uk/pdbsum/6exq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6exq ProSAT]</span></td></tr>
</table>
<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 &lt; 10 nM), preventing the cell-growth of T. b. rhodesiense (IC50 &lt; 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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6exq" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Trypanosoma brucei rhodesiense]]
[[Category: Dietzel U]]
[[Category: Kisker C]]