7s18: Difference between revisions
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==Crystal structure of cruzain with gallinamide analog from 2-biaryl series== | ==Crystal structure of cruzain with gallinamide analog from 2-biaryl series== | ||
<StructureSection load='7s18' size='340' side='right'caption='[[7s18]]' scene=''> | <StructureSection load='7s18' size='340' side='right'caption='[[7s18]], [[Resolution|resolution]] 2.14Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7S18 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7S18 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7s18]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7S18 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7S18 FirstGlance]. <br> | ||
</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=7s18 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7s18 OCA], [https://pdbe.org/7s18 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7s18 RCSB], [https://www.ebi.ac.uk/pdbsum/7s18 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7s18 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=83E:N,N-dimethyl-L-valyl-L-leucyl-N-[(3S)-6-{(2S)-2-[([1,1-biphenyl]-4-yl)methyl]-3-methoxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl}-6-oxo-1-phenylhexan-3-yl]-L-leucinamide'>83E</scene></td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Cruzipain Cruzipain], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.51 3.4.22.51] </span></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=7s18 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7s18 OCA], [https://pdbe.org/7s18 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7s18 RCSB], [https://www.ebi.ac.uk/pdbsum/7s18 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7s18 ProSAT]</span></td></tr> | |||
</table> | </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 == | |||
Gallinamide A, a metabolite of the marine cyanobacterium Schizothrix sp., selectively inhibits cathepsin L-like cysteine proteases. We evaluated the potency of gallinamide A and 23 synthetic analogues against intracellular Trypanosoma cruzi amastigotes and the cysteine protease, cruzain. We determined the co-crystal structures of cruzain with gallinamide A and two synthetic analogues at approximately 2 A. SAR data revealed that the N-terminal end of gallinamide A is loosely bound and weakly contributes in drug-target interactions. At the C-terminus, the intramolecular pi-pi stacking interactions between the aromatic substituents at P1' and P1 restrict the bioactive conformation of the inhibitors, thus minimizing the entropic loss associated with target binding. Molecular dynamics simulations showed that in the absence of an aromatic group at P1, the substituent at P1' interacts with tryptophan-184. The P1-P1' interactions had no effect on anti-cruzain activity, whereas anti-T. cruzi potency increased by approximately fivefold, likely due to an increase in solubility/permeability of the analogues. | |||
Intramolecular Interactions Enhance the Potency of Gallinamide A Analogues against Trypanosoma cruzi.,Barbosa Da Silva E, Sharma V, Hernandez-Alvarez L, Tang AH, Stoye A, O'Donoghue AJ, Gerwick WH, Payne RJ, McKerrow JH, Podust LM J Med Chem. 2022 Feb 21. doi: 10.1021/acs.jmedchem.1c02063. PMID:35188371<ref>PMID:35188371</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7s18" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Cruzipain]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Podust | [[Category: Podust, L M]] | ||
[[Category: Sharma V]] | [[Category: Sharma, V]] | ||
[[Category: Cruzain]] | |||
[[Category: Cysteine protease]] | |||
[[Category: Gallinamide]] | |||
[[Category: Hydrolase]] | |||
Revision as of 15:00, 23 March 2022
Crystal structure of cruzain with gallinamide analog from 2-biaryl seriesCrystal structure of cruzain with gallinamide analog from 2-biaryl series
Structural highlights
Function[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. Publication Abstract from PubMedGallinamide A, a metabolite of the marine cyanobacterium Schizothrix sp., selectively inhibits cathepsin L-like cysteine proteases. We evaluated the potency of gallinamide A and 23 synthetic analogues against intracellular Trypanosoma cruzi amastigotes and the cysteine protease, cruzain. We determined the co-crystal structures of cruzain with gallinamide A and two synthetic analogues at approximately 2 A. SAR data revealed that the N-terminal end of gallinamide A is loosely bound and weakly contributes in drug-target interactions. At the C-terminus, the intramolecular pi-pi stacking interactions between the aromatic substituents at P1' and P1 restrict the bioactive conformation of the inhibitors, thus minimizing the entropic loss associated with target binding. Molecular dynamics simulations showed that in the absence of an aromatic group at P1, the substituent at P1' interacts with tryptophan-184. The P1-P1' interactions had no effect on anti-cruzain activity, whereas anti-T. cruzi potency increased by approximately fivefold, likely due to an increase in solubility/permeability of the analogues. Intramolecular Interactions Enhance the Potency of Gallinamide A Analogues against Trypanosoma cruzi.,Barbosa Da Silva E, Sharma V, Hernandez-Alvarez L, Tang AH, Stoye A, O'Donoghue AJ, Gerwick WH, Payne RJ, McKerrow JH, Podust LM J Med Chem. 2022 Feb 21. doi: 10.1021/acs.jmedchem.1c02063. PMID:35188371[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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