6pf9: Difference between revisions
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<StructureSection load='6pf9' size='340' side='right'caption='[[6pf9]], [[Resolution|resolution]] 2.89Å' scene=''> | <StructureSection load='6pf9' size='340' side='right'caption='[[6pf9]], [[Resolution|resolution]] 2.89Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6pf9]] is a 5 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PF9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PF9 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6pf9]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Cryho Cryho]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PF9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PF9 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MTX:METHOTREXATE'>MTX</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=OF7:[2-({4-[(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl]benzene-1-carbonyl}amino)phenyl]acetic+acid'>OF7</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UFP:5-FLUORO-2-DEOXYURIDINE-5-MONOPHOSPHATE'>UFP</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MTX:METHOTREXATE'>MTX</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=OF7:[2-({4-[(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl]benzene-1-carbonyl}amino)phenyl]acetic+acid'>OF7</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UFP:5-FLUORO-2-DEOXYURIDINE-5-MONOPHOSPHATE'>UFP</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CHUDEA4_4460 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=237895 CRYHO])</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=6pf9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pf9 OCA], [http://pdbe.org/6pf9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pf9 RCSB], [http://www.ebi.ac.uk/pdbsum/6pf9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pf9 ProSAT]</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=6pf9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pf9 OCA], [http://pdbe.org/6pf9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pf9 RCSB], [http://www.ebi.ac.uk/pdbsum/6pf9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pf9 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Cryho]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Anderson, K S]] | [[Category: Anderson, K S]] | ||
Revision as of 15:24, 18 December 2019
Crystal structure of TS-DHFR from Cryptosporidium hominis in complex with NADPH, FdUMP and 2-(2-(4-((2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl)benzamido)phenyl)acetic acid.Crystal structure of TS-DHFR from Cryptosporidium hominis in complex with NADPH, FdUMP and 2-(2-(4-((2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl)benzamido)phenyl)acetic acid.
Structural highlights
Function[A0A0S4TER9_CRYHO] Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism.[PIRNR:PIRNR000389] Publication Abstract from PubMedCryptosporidiosis is a human gastrointestinal disease caused by protozoans of the genus Cryptosporidium, which can be fatal in immunocompromised individuals. The essential enzyme, thymidylate synthase (TS), is responsible for de novo synthesis of deoxythymidine monophosphate. The TS active site is relatively conserved between Cryptosporidium and human enzymes. In previous work, we identified compound 1, (2-amino-4-oxo-4,7-dihydro-pyrrolo[2,3-d]pyrimidin-methyl-phenyl-l-glutamic acid), as a promising selective Cryptosporidium hominis TS (ChTS) inhibitor. In the present study, we explore the structure-activity relationship around 1 glutamate moiety by synthesizing and biochemically evaluating the inhibitory activity of analogues against ChTS and human TS (hTS). X-Ray crystal structures were obtained for compounds bound to both ChTS and hTS. We establish the importance of the 2-phenylacetic acid moiety methylene linker in optimally positioning compounds 23, 24, and 25 within the active site. Moreover, through the comparison of structural data for 5, 14, 15, and 23 bound in both ChTS and hTS identified that active site rigidity is a driving force in determining inhibitor selectivity. Structure activity relationship towards design of cryptosporidium specific thymidylate synthase inhibitors.,Czyzyk DJ, Valhondo M, Deiana L, Tirado-Rives J, Jorgensen WL, Anderson KS Eur J Med Chem. 2019 Sep 4;183:111673. doi: 10.1016/j.ejmech.2019.111673. PMID:31536894[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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