3td8: Difference between revisions
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==Structural Analysis of Pneumocystis carinii Dihydrofolate Reductase Complex with NADPH and 2,4-diamino-5-methyl-6-[2'-(4-carboxy-1-pentynyl)-5'-methoxybenzyl]pyrido[2,3-d]pyrimidine== | |||
<StructureSection load='3td8' size='340' side='right' caption='[[3td8]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3td8]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Pneca Pneca]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TD8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TD8 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=D2R:6-{2-[(2,4-DIAMINO-5-METHYLPYRIDO[2,3-D]PYRIMIDIN-6-YL)METHYL]-4-METHOXYPHENYL}HEX-5-YNOIC+ACID'>D2R</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3cd2|3cd2]]</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=3td8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3td8 OCA], [http://pdbe.org/3td8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3td8 RCSB], [http://www.ebi.ac.uk/pdbsum/3td8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3td8 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/DYR_PNECA DYR_PNECA]] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Structural data are reported for 2,4-diamino-6-[2-(5-carboxypent-1-yn-1-yl)-5-methoxybenzyl]-5-methylpyrido[2,3-d] pyrimidine (PY1014) complexed with Pneumocystis carinii dihydrofolate reductase (pcDHFR) refined to 1.8 A resolution. These data reveal that the carboxylate of the omega-carboxyalkynyl side chain of PY1014, the most pcDHFR-selective analog in this series, forms ionic interactions with the conserved Arg75 in the substrate-binding pocket of pcDHFR. The reversal of the 2',5'-substitution pattern of this analog compared with the highly selective diaminopyrimidine analog PY1011 (i.e. the 5'-pentynylcarboxy-5'-methoxy pattern of PY1014 versus the 3',4'-dimethoxy-5'-pentynylcarboxy pattern of PY1011) is necessary to achieve optimal interaction with Arg75 as observed in other structures. The larger diaminopyrido[2,3-d]pyrimidine ring of PY1014 places the 5'-methoxy group closer to Leu25 and Ser64 than does the diaminopyrimidine ring of PY1011. The 5'-methoxy O atom forms a hydrogen bond to the amide of Leu25 (O...N, 2.7 A) and the 5'-methoxy methyl group makes a hydrophobic contact of 3.1 A with C(beta) of Ser64. Although the IC(50) values of PY1014 and PY1011 are similar, inhibition data show that the selectivity of PY1011 for pcDHFR is significantly greater. The greater selectivity for pcDHFR compared with mammalian DHFR of these inhibitors is also influenced by the enhanced hydrophobic interactions of the side-chain methylene atoms with Phe69 of pcDHFR compared with Asn64 of mammalian DHFR. | |||
Structural analysis of Pneumocystis cariniidihydrofolate reductase complexed with NADPH and 2,4-diamino-6-[2-(5-carboxypent-1-yn-1-yl)-5-methoxybenzyl]-5-methylpyrido[2,3-d] pyrimidine.,Cody V, Pace J, Stewart E Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Apr 1;68(Pt 4):418-23., Epub 2012 Mar 28. PMID:22505410<ref>PMID:22505410</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3td8" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Dihydrofolate reductase|Dihydrofolate reductase]] | *[[Dihydrofolate reductase|Dihydrofolate reductase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Dihydrofolate reductase]] | [[Category: Dihydrofolate reductase]] | ||
[[Category: Pneca]] | |||
[[Category: Cody, V]] | |||
[[Category: Pace, J]] | |||
[[Category: Stewart, E]] | |||
[[Category: Oxidoreductase]] | [[Category: Oxidoreductase]] | ||
Latest revision as of 10:42, 4 August 2016
Structural Analysis of Pneumocystis carinii Dihydrofolate Reductase Complex with NADPH and 2,4-diamino-5-methyl-6-[2'-(4-carboxy-1-pentynyl)-5'-methoxybenzyl]pyrido[2,3-d]pyrimidineStructural Analysis of Pneumocystis carinii Dihydrofolate Reductase Complex with NADPH and 2,4-diamino-5-methyl-6-[2'-(4-carboxy-1-pentynyl)-5'-methoxybenzyl]pyrido[2,3-d]pyrimidine
Structural highlights
Function[DYR_PNECA] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Publication Abstract from PubMedStructural data are reported for 2,4-diamino-6-[2-(5-carboxypent-1-yn-1-yl)-5-methoxybenzyl]-5-methylpyrido[2,3-d] pyrimidine (PY1014) complexed with Pneumocystis carinii dihydrofolate reductase (pcDHFR) refined to 1.8 A resolution. These data reveal that the carboxylate of the omega-carboxyalkynyl side chain of PY1014, the most pcDHFR-selective analog in this series, forms ionic interactions with the conserved Arg75 in the substrate-binding pocket of pcDHFR. The reversal of the 2',5'-substitution pattern of this analog compared with the highly selective diaminopyrimidine analog PY1011 (i.e. the 5'-pentynylcarboxy-5'-methoxy pattern of PY1014 versus the 3',4'-dimethoxy-5'-pentynylcarboxy pattern of PY1011) is necessary to achieve optimal interaction with Arg75 as observed in other structures. The larger diaminopyrido[2,3-d]pyrimidine ring of PY1014 places the 5'-methoxy group closer to Leu25 and Ser64 than does the diaminopyrimidine ring of PY1011. The 5'-methoxy O atom forms a hydrogen bond to the amide of Leu25 (O...N, 2.7 A) and the 5'-methoxy methyl group makes a hydrophobic contact of 3.1 A with C(beta) of Ser64. Although the IC(50) values of PY1014 and PY1011 are similar, inhibition data show that the selectivity of PY1011 for pcDHFR is significantly greater. The greater selectivity for pcDHFR compared with mammalian DHFR of these inhibitors is also influenced by the enhanced hydrophobic interactions of the side-chain methylene atoms with Phe69 of pcDHFR compared with Asn64 of mammalian DHFR. Structural analysis of Pneumocystis cariniidihydrofolate reductase complexed with NADPH and 2,4-diamino-6-[2-(5-carboxypent-1-yn-1-yl)-5-methoxybenzyl]-5-methylpyrido[2,3-d] pyrimidine.,Cody V, Pace J, Stewart E Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Apr 1;68(Pt 4):418-23., Epub 2012 Mar 28. PMID:22505410[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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