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| | <StructureSection load='3s7a' size='340' side='right'caption='[[3s7a]], [[Resolution|resolution]] 1.80Å' scene=''> | | <StructureSection load='3s7a' size='340' side='right'caption='[[3s7a]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3s7a]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S7A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3S7A FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3s7a]] is a 1 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=3S7A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3S7A FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=684:4-({5-[(2,4-DIAMINOPTERIDIN-6-YL)METHYL]-5H-DIBENZO[B,F]AZEPIN-2-YL}OXY)BUTANOIC+ACID'>684</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DHFR ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=684:4-({5-[(2,4-DIAMINOPTERIDIN-6-YL)METHYL]-5H-DIBENZO[B,F]AZEPIN-2-YL}OXY)BUTANOIC+ACID'>684</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] </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=3s7a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s7a OCA], [https://pdbe.org/3s7a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3s7a RCSB], [https://www.ebi.ac.uk/pdbsum/3s7a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3s7a ProSAT]</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=3s7a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s7a OCA], [https://pdbe.org/3s7a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3s7a RCSB], [https://www.ebi.ac.uk/pdbsum/3s7a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3s7a ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == 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>
| + | [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 == | | == 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>
| + | [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 ==
| + | |
| - | In order to understand the structure-activity profile observed for a series of substituted dibenz[b,f]azepine antifolates, the crystal structure of the binary complex of human dihydrofolate reductase (hDHFR) with the potent and selective inhibitor 2,4-diamino-6-{2'-O-(3-carboxypropyl)oxydibenz[b,f]-azepin-5-yl}methylpter idine (PT684) was determined to 1.8 A resolution. These data revealed that the carboxylate side chain of PT684 occupies two alternate positions, neither of which interacts with the conserved Arg70 in the active-site pocket, which in turn hydrogen bonds to water. These observations are in contrast to those reported for the ternary complex of mouse DHFR (mDHFR) with NADPH [Cody et al. (2008), Acta Cryst. D64, 977-984], in which the 3-carboxypropyl side chain of PT684 was hydrolyzed to its hydroxyl derivative, PT684a. The crystallization conditions differed for the human and mouse DHFR crystals (100 mM K(2)HPO(4) pH 6.9, 30% ammonium sulfate for hDHFR; 15 mM Tris pH 8.3, 75 mM sodium cacodylate, PEG 4K for mDHFR). Additionally, the side chains of Phe31 and Gln35 in the hDHFR complex have a single conformation, whereas in the mDHFR complex they occupied two alternative conformations. These data show that the hDHFR complex has a decreased active-site volume compared with the mDHFR complex, as reflected in a relative shift of helix C (residues 59-64) of 1.2 A, and a shift of 1.5 A compared with the ternary complex of Pneumocystis carinii DHFR (pcDHFR) with the parent dibenz[b,f]azepine PT653. These data suggest that the greater inhibitory potency of PT684 against pcDHFR is consistent with the larger active-site volume of pcDHFR and the predicted interactions of the carboxylate side chain with Arg75.
| + | |
| - | | + | |
| - | Structural analysis of human dihydrofolate reductase as a binary complex with the potent and selective inhibitor 2,4-diamino-6-{2'-O-(3-carboxypropyl)oxydibenz[b,f]-azepin-5-yl}methylpter idine reveals an unusual binding mode.,Cody V, Pace J, Nowak J Acta Crystallogr D Biol Crystallogr. 2011 Oct;67(Pt 10):875-80. Epub 2011, Sep 8. PMID:21931219<ref>PMID:21931219</ref>
| + | |
| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 3s7a" style="background-color:#fffaf0;"></div>
| + | |
| | | | |
| | ==See Also== | | ==See Also== |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Dihydrofolate reductase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Cody, V]] | + | [[Category: Cody V]] |
| - | [[Category: Nowak, J]] | + | [[Category: Nowak J]] |
| - | [[Category: Pace, J]] | + | [[Category: Pace J]] |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
| - | [[Category: Reductase]]
| + | |
| - | [[Category: Single polypeptide chain]]
| + | |
| Structural highlights
Disease
DYR_HUMAN Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM: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.[1] [2]
Function
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.[3] [4]
See Also
References
- ↑ Banka S, Blom HJ, Walter J, Aziz M, Urquhart J, Clouthier CM, Rice GI, de Brouwer AP, Hilton E, Vassallo G, Will A, Smith DE, Smulders YM, Wevers RA, Steinfeld R, Heales S, Crow YJ, Pelletier JN, Jones S, Newman WG. Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency. Am J Hum Genet. 2011 Feb 11;88(2):216-25. doi: 10.1016/j.ajhg.2011.01.004. PMID:21310276 doi:10.1016/j.ajhg.2011.01.004
- ↑ Cario H, Smith DE, Blom H, Blau N, Bode H, Holzmann K, Pannicke U, Hopfner KP, Rump EM, Ayric Z, Kohne E, Debatin KM, Smulders Y, Schwarz K. Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease. Am J Hum Genet. 2011 Feb 11;88(2):226-31. doi: 10.1016/j.ajhg.2011.01.007. PMID:21310277 doi:10.1016/j.ajhg.2011.01.007
- ↑ Anderson DD, Quintero CM, Stover PJ. Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria. Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15163-8. doi:, 10.1073/pnas.1103623108. Epub 2011 Aug 26. PMID:21876188 doi:10.1073/pnas.1103623108
- ↑ Klon AE, Heroux A, Ross LJ, Pathak V, Johnson CA, Piper JR, Borhani DW. Atomic structures of human dihydrofolate reductase complexed with NADPH and two lipophilic antifolates at 1.09 a and 1.05 a resolution. J Mol Biol. 2002 Jul 12;320(3):677-93. PMID:12096917
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