View source for 4qh6


==Crystal structure of cruzain with nitrile inhibitor N-(2-AMINOETHYL)-NALPHA-BENZOYL-L-PHENYLALANINAMIDE==
<StructureSection load='4qh6' size='340' side='right'caption='[[4qh6]], [[Resolution|resolution]] 3.13&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4qh6]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_cruzi Trypanosoma cruzi]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QH6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QH6 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]] 3.13&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=33L:N-(2-AMINOETHYL)-NALPHA-BENZOYL-L-PHENYLALANINAMIDE'>33L</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=4qh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qh6 OCA], [https://pdbe.org/4qh6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qh6 RCSB], [https://www.ebi.ac.uk/pdbsum/4qh6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qh6 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CYSP_TRYCR CYSP_TRYCR] Hydrolyzes chromogenic peptides at the carboxyl Arg or Lys; requires at least one more amino acid, preferably Arg, Phe, Val or Leu, between the terminal Arg or Lys and the amino-blocking group.  The cysteine protease may play an important role in the development and differentiation of the parasites at several stages of their life cycle.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
A series of compounds based on the dipeptidyl nitrile scaffold were synthesized and assayed for their inhibitory activity against the T. cruzi cysteine protease cruzain. Structure activity relationships (SARs) were established using three, eleven and twelve variations respectively at the P1, P2 and P3 positions. A Ki value of 16 nM was observed for the most potent of these inhibitors which reflects a degree of non-additivity in the SAR. An X-ray crystal structure was determined for the ligand-protein complex for the structural prototype for the series. Twenty three inhibitors were also evaluated for their anti-trypanosomal effects and an EC50 value of 28 muM was observed for the most potent of these. Although there remains scope for further optimization, the knowledge gained from this study is also transferable to the design of cruzain inhibitors based on warheads other than nitrile as well as alternative scaffolds.

Molecular Design, Synthesis and Trypanocidal Activity of Dipeptidyl Nitriles as Cruzain Inhibitors.,Avelar LA, Camilo CD, de Albuquerque S, Fernandes WB, Goncalez C, Kenny PW, Leitao A, McKerrow JH, Montanari CA, Orozco EV, Ribeiro JF, Rocha JR, Rosini F, Saidel ME PLoS Negl Trop Dis. 2015 Jul 14;9(7):e0003916. doi: 10.1371/journal.pntd.0003916., eCollection 2015 Jul. PMID:26173110<ref>PMID:26173110</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4qh6" style="background-color:#fffaf0;"></div>

==See Also==
*[[Cruzain|Cruzain]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Trypanosoma cruzi]]
[[Category: Fernandes WB]]
[[Category: McKerrow JH]]
[[Category: Montanari CA]]