View source for 6spt


==High resolution crystal structure of N-terminal domain of PEX14 from Trypanosoma brucei in complex with the fist compound with sub-micromolar trypanocidal activity==
<StructureSection load='6spt' size='340' side='right'caption='[[6spt]], [[Resolution|resolution]] 1.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6spt]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei_brucei Trypanosoma brucei brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6SPT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SPT 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]] 1.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FTW:5-[(4-methoxynaphthalen-1-yl)methyl]-1-[2-[(2-methyl-1-oxidanyl-propan-2-yl)amino]ethyl]-~{N}-(naphthalen-1-ylmethyl)-6,7-dihydro-4~{H}-pyrazolo[4,3-c]pyridine-3-carboxamide'>FTW</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=6spt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6spt OCA], [https://pdbe.org/6spt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6spt RCSB], [https://www.ebi.ac.uk/pdbsum/6spt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6spt ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q8IEW2_TRYBB Q8IEW2_TRYBB] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Trypanosoma protists are pathogens leading to a spectrum of devastating infectious diseases. The range of available chemotherapeutics against Trypanosoma is limited and the existing therapies are partially ineffective and cause serious adverse effects. Formation of the PEX14-PEX5 complex is essential for protein import into the parasites' glycosomes. This transport is critical for parasite metabolism and failure leads to mislocalization of glycosomal enzymes, with fatal consequences for the parasite. Hence, inhibiting the PEX14-PEX5 protein-protein interaction (PPI) is an attractive way to affect multiple metabolic pathways. Herein, we have used structure-guided computational screening and optimization to develop the first line of compounds that inhibit PEX14-PEX5 protein-protein interaction. The optimization was driven by several X-ray structures, NMR binding data and molecular dynamics simulations. Importantly, the developed compounds show significant cellular activity against Trypanosoma, including the human pathogen T. brucei gambiense and T. cruzi parasites.

Structure-activity relationship in pyrazolo[4,3-c]pyridines, first inhibitors of PEX14-PEX5 Protein-Protein Interaction (PPI) with trypanocidal activity.,Dawidowski M, Kalel VC, Napolitano V, Fino R, Schorpp K, Emmanouilidis L, Lenhart D, Ostertag M, Kaiser M, Kolonko M, Tippler B, Schliebs W, Dubin G, Maser P, Tetko I, Hadian K, Plettenburg O, Erdmann R, Sattler M, Popowicz GM J Med Chem. 2019 Dec 20. doi: 10.1021/acs.jmedchem.9b01876. PMID:31860309<ref>PMID:31860309</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6spt" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Trypanosoma brucei brucei]]
[[Category: Dawidowski M]]
[[Category: Dubin G]]
[[Category: Emmanouilidis L]]
[[Category: Erdmann R]]
[[Category: Fino R]]
[[Category: Hadian K]]
[[Category: Kaiser M]]
[[Category: Kalel VC]]
[[Category: Kolonko M]]
[[Category: Lenhart D]]
[[Category: Maser P]]
[[Category: Napolitano V]]
[[Category: Ostertag M]]
[[Category: Plettenburg O]]
[[Category: Popowicz GM]]
[[Category: Sattler M]]
[[Category: Schilebs W]]
[[Category: Tetko I]]