6pfg: Difference between revisions

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

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-'''Unreleased structure'''
-The entry 6pfg is ON HOLD  until Paper Publication
+==Crystal structure of TS-DHFR from Cryptosporidium hominis in complex with NADPH, FdUMP and 2-(4-((2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl)benzamido)-4-carbamoylbenzoic acid.==
+<StructureSection load='6pfg' size='340' side='right'caption='[[6pfg]], [[Resolution|resolution]] 2.71&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6pfg]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Cryptosporidium_hominis Cryptosporidium hominis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PFG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PFG 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]] 2.706&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MTX:METHOTREXATE'>MTX</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=OFJ:2-({4-[(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl]benzene-1-carbonyl}amino)-4-carbamoylbenzoic+acid'>OFJ</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6pfg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pfg OCA], [https://pdbe.org/6pfg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pfg RCSB], [https://www.ebi.ac.uk/pdbsum/6pfg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pfg ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/A0A0S4TER9_CRYHO A0A0S4TER9_CRYHO] Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism.[PIRNR:PIRNR000389]
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Cryptosporidiosis 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.
-Authors: Czyzyk, D.J., Valhondo, M., Jorgensen, W.L., Anderson, K.S.
+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<ref>PMID:31536894</ref>
-Description: Crystal structure of TS-DHFR from Cryptosporidium hominis in complex with NADPH, FdUMP and 2-(4-((2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl)benzamido)-4-carbamoylbenzoic acid.
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Valhondo, M]]
+<div class="pdbe-citations 6pfg" style="background-color:#fffaf0;"></div>
-[[Category: Czyzyk, D.J]]
-[[Category: Anderson, K.S]]
+==See Also==
-[[Category: Jorgensen, W.L]]
+*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Cryptosporidium hominis]]
+[[Category: Large Structures]]
+[[Category: Anderson KS]]
+[[Category: Czyzyk DJ]]
+[[Category: Jorgensen WL]]
+[[Category: Valhondo M]]