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3nxt

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Revision as of 14:37, 5 August 2016

Preferential Selection of Isomer Binding from Chiral Mixtures: Alternate Binding Modes Observed for the E-and Z-isomers of a Series of 5-substituted 2,4-diaminofuro[2m,3-d]pyrimidines as Ternary Complexes with NADPH and Human Dihydrofolate Reductase

Structural highlights

3nxt is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	3nxo, 3nxr, 3nxv, 3nxx, 3nxy, 3nz6, 3nz9, 3nza, 3nzb, 3nzc, 3nzd, 3gyf, 3d7y, 3d7x
Gene:	DHFR, DHFRP1 (HUMAN)
Activity:	Dihydrofolate reductase, with EC number 1.5.1.3
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

The crystal structures of six human dihydrofolate reductase (hDHFR) ternary complexes with NADPH and a series of mixed E/Z isomers of 5-substituted 5-[2-(2-methoxyphenyl)-prop-1-en-1-yl]furo[2,3-d]pyrimidine-2,4-diamines substituted at the C9 position with propyl, isopropyl, cyclopropyl, butyl, isobutyl and sec-butyl (E2-E7, Z3) were determined and the results were compared with the resolved E and Z isomers of the C9-methyl parent compound. The configuration of all of the inhibitors, save one, was observed as the E isomer, in which the binding of the furopyrimidine ring is flipped such that the 4-amino group binds in the 4-oxo site of folate. The Z3 isomer of the C9-isopropyl analog has the normal 2,4-diaminopyrimidine ring binding geometry, with the furo oxygen near Glu30 and the 4-amino group interacting near the cofactor nicotinamide ring. Electron-density maps for these structures revealed the binding of only one isomer to hDHFR, despite the fact that chiral mixtures (E:Z ratios of 2:1, 3:1 and 3:2) of the inhibitors were incubated with hDHFR prior to crystallization. Superposition of the hDHFR complexes with E2 and Z3 shows that the 2'-methoxyphenyl ring of E2 is perpendicular to that of Z3. The most potent inhibitor in this series is the isopropyl analog Z3 and the least potent is the isobutyl analog E6, consistent with data that show that the Z isomer makes the most favorable interactions with the active-site residues. The isobutyl moiety of E6 is observed in two orientations and the resultant steric crowding of the E6 analog is consistent with its weaker activity. The alternative binding modes observed for the furopyrimidine ring in these E/Z isomers suggest that new templates can be designed to probe these binding regions of the DHFR active site.

Preferential selection of isomer binding from chiral mixtures: alternate binding modes observed for the E and Z isomers of a series of 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines as ternary complexes with NADPH and human dihydrofolate reductase.,Cody V, Piraino J, Pace J, Li W, Gangjee A Acta Crystallogr D Biol Crystallogr. 2010 Dec;66(Pt 12):1271-7. Epub 2010, Nov 16. PMID:21123866^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Cody V, Piraino J, Pace J, Li W, Gangjee A. Preferential selection of isomer binding from chiral mixtures: alternate binding modes observed for the E and Z isomers of a series of 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines as ternary complexes with NADPH and human dihydrofolate reductase. Acta Crystallogr D Biol Crystallogr. 2010 Dec;66(Pt 12):1271-7. Epub 2010, Nov 16. PMID:21123866 doi:10.1107/S0907444910035808

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3nxt"

Categories: Dihydrofolate reductase | Human | Cody, V | Chiral selectivity e-z-isomer | Oxidoreductase

@@ Line 1: / Line 1: @@
 ==Preferential Selection of Isomer Binding from Chiral Mixtures: Alternate Binding Modes Observed for the E-and Z-isomers of a Series of 5-substituted 2,4-diaminofuro[2m,3-d]pyrimidines as Ternary Complexes with NADPH and Human Dihydrofolate Reductase==
 <StructureSection load='3nxt' size='340' side='right' caption='[[3nxt]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3nxt]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3NXT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3NXT FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3nxt]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3NXT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3NXT FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=D2E:5-[(E)-2-CYCLOPROPYL-2-(2-METHOXYPHENYL)ETHENYL]FURO[2,3-D]PYRIMIDINE-2,4-DIAMINE'>D2E</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3nxo|3nxo]], [[3nxr|3nxr]], [[3nxv|3nxv]], [[3nxx|3nxx]], [[3nxy|3nxy]], [[3nz6|3nz6]], [[3nz9|3nz9]], [[3nza|3nza]], [[3nzb|3nzb]], [[3nzc|3nzc]], [[3nzd|3nzd]], [[3gyf|3gyf]], [[3d7y|3d7y]], [[3d7x|3d7x]]</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DHFR, DHFRP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DHFR, DHFRP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3nxt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nxt OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3nxt RCSB], [http://www.ebi.ac.uk/pdbsum/3nxt PDBsum]</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=3nxt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nxt OCA], [http://pdbe.org/3nxt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3nxt RCSB], [http://www.ebi.ac.uk/pdbsum/3nxt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3nxt ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 21: / Line 22: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3nxt" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 29: / Line 31: @@
 </StructureSection>
 [[Category: Dihydrofolate reductase]]
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Cody, V]]
 [[Category: Chiral selectivity e-z-isomer]]
 [[Category: Oxidoreductase]]

3nxt

From Proteopedia

Revision as of 14:37, 5 August 2016

Preferential Selection of Isomer Binding from Chiral Mixtures: Alternate Binding Modes Observed for the E-and Z-isomers of a Series of 5-substituted 2,4-diaminofuro[2m,3-d]pyrimidines as Ternary Complexes with NADPH and Human Dihydrofolate Reductase

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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