6vcj
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 6vcj is ON HOLD Authors: Description: Category: Unreleased Structures) |
|||
| (5 intermediate revisions not shown.) | |||
| Line 1: | Line 1: | ||
| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of hsDHFR in complex with NADP+, DAP, and R-naproxen== | |
| + | <StructureSection load='6vcj' size='340' side='right'caption='[[6vcj]], [[Resolution|resolution]] 2.34Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6vcj]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VCJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VCJ 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]] 2.34Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FOL:FOLIC+ACID'>FOL</scene>, <scene name='pdbligand=LG3:PYRIMIDINE-2,4-DIAMINE'>LG3</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=NPX:(2R)-2-(6-METHOXYNAPHTHALEN-2-YL)PROPANOIC+ACID'>NPX</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=6vcj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vcj OCA], [https://pdbe.org/6vcj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vcj RCSB], [https://www.ebi.ac.uk/pdbsum/6vcj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vcj ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN] Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:[https://omim.org/entry/613839 613839]. DHFRD is an inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.<ref>PMID:21310276</ref> <ref>PMID:21310277</ref> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN] Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.<ref>PMID:21876188</ref> <ref>PMID:12096917</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Although nonsteroidal anti-inflammatory drugs (NSAIDs) target primarily cyclooxygenase enzymes, a subset of NSAIDs containing carboxylate groups also has been reported to competitively inhibit dihydrofolate reductase (DHFR). In this study, we have characterized NSAID interactions with human DHFR based on kinetic, NMR, and X-ray crystallographic methods. The NSAIDs target a region of the folate binding site that interacts with the p-aminobenzoyl-l-glutamate (pABG) moiety of folate and inhibit cooperatively with ligands that target the adjacent pteridine-recognition subsite. NSAIDs containing benzoate or salicylate groups were identified as having the highest potency. Among those tested, diflunisal, a salicylate derivative not previously identified to have anti-folate activity, was found to have a Ki of 34 muM, well below peak plasma diflunisal levels reached at typical dosage levels. The potential of these drugs to interfere with the inflammatory process by multiple pathways introduces the possibility of further optimization to design dual-targeted analogs. | ||
| - | + | The Structural Basis for Nonsteroidal Anti-Inflammatory Drug Inhibition of Human Dihydrofolate Reductase.,Duff MR Jr, Gabel SA, Pedersen LC, DeRose EF, Krahn JM, Howell EE, London RE J Med Chem. 2020 Aug 13;63(15):8314-8324. doi: 10.1021/acs.jmedchem.0c00546. Epub, 2020 Jul 28. PMID:32658475<ref>PMID:32658475</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6vcj" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: DeRose EF]] | ||
| + | [[Category: Gabel SA]] | ||
| + | [[Category: Krahn JM]] | ||
| + | [[Category: London RE]] | ||
| + | [[Category: Pedersen LC]] | ||
Current revision
Crystal structure of hsDHFR in complex with NADP+, DAP, and R-naproxen
| |||||||||||
