1mvs: Difference between revisions

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New page: left|200px<br /> <applet load="1mvs" size="450" color="white" frame="true" align="right" spinBox="true" caption="1mvs, resolution 1.90Å" /> '''Analysis of Two Pol...
 
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[[Image:1mvs.gif|left|200px]]<br />
<applet load="1mvs" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1mvs, resolution 1.90&Aring;" />
'''Analysis of Two Polymorphic Forms of a Pyrido[2,3-d]pyrimidine N9-C10 Reverse-Bridge Antifolate Binary Complex with Human Dihydrofolate Reductase'''<br />


==Overview==
==Analysis of Two Polymorphic Forms of a Pyrido[2,3-d]pyrimidine N9-C10 Reverse-Bridge Antifolate Binary Complex with Human Dihydrofolate Reductase==
The results of the crystal structure determination of human dihydrofolate, reductase (hDHFR) as a binary complex with the potent N9-C10, reversed-bridge antifolate inhibitor, 2,4-diamino-6-[N-(3',4',5'-trimethoxybenzyl)-N-methylamino]pyrido[2,3-d]py, rimidine (1) are reported for two independent polymorphic rhombohedral R3, lattices [R3(1) and R3(2)]. Data from these two crystal forms were refined, to 1.90 A resolution for complex R3(1), with R = 0.186 for 9689 data, and, to 1.80 A resolution for complex R3(2), with R = 0.194 for 13 305 data., Changes in the loop geometry between the two structures reflects contact, differences in the packing environments in the two R3 lattices. The, largest changes (between 0.5 and 1.7 A) are observed for the loop regions, encompassing residues 16-25, 40-48, 81-89, 99-108, 143-148 and 161-169., Comparison of the intermolecular contacts of these loops reveals that the, R3(2) lattice is more tightly packed, as reflected in its smaller V(M), value and smaller solvent content. The conformation of inhibitor (1) is, similar in both structures and the N9-C10 bridge geometry is more similar, to that observed for the normal C9-N10 bridge of trimetrexate (TMQ) than, to the other N9-C10 reversed-bridge antifolates previously reported. The, effect of the N9-C10 reversed-bridge geometry is to distort the bridge, from coplanarity with the pyrido[2,3-d]pyrimidine ring system and to twist, the C10 methylene conformation towards a gauche conformation. This also, influences the conformation of the methoxybenzyl ring, moving it away from, a trans position and placing the 5'-methoxy group deeper within the, hydrophobic pocket made by Leu60, Pro61 and Asn64 of the hDHFR active, site.
<StructureSection load='1mvs' size='340' side='right'caption='[[1mvs]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1mvs]] 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=1MVS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1MVS 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]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DTM:2,4-DIAMINO-6-[N-(3,4,5-TRIMETHOXYBENZYL)-N-METHYLAMINO]PYRIDO[2,3-D]PYRIMIDINE'>DTM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=1mvs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1mvs OCA], [https://pdbe.org/1mvs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1mvs RCSB], [https://www.ebi.ac.uk/pdbsum/1mvs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1mvs 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>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/mv/1mvs_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1mvs ConSurf].
<div style="clear:both"></div>


==Disease==
==See Also==
Known disease associated with this structure: Anemia, megaloblastic, due to DHFR deficiency (1) OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=126060 126060]]
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
 
== References ==
==About this Structure==
<references/>
1MVS is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4 and DTM as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1MVS OCA].
__TOC__
 
</StructureSection>
==Reference==
Analysis of two polymorphic forms of a pyrido[2,3-d]pyrimidine N9-C10 reversed-bridge antifolate binary complex with human dihydrofolate reductase., Cody V, Galitsky N, Luft JR, Pangborn W, Gangjee A, Acta Crystallogr D Biol Crystallogr. 2003 Apr;59(Pt 4):654-61. Epub 2003, Mar 25. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12657784 12657784]
[[Category: Dihydrofolate reductase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Cody, V.]]
[[Category: Cody V]]
[[Category: Galitsky, N.]]
[[Category: Galitsky N]]
[[Category: Gangjee, A.]]
[[Category: Gangjee A]]
[[Category: Luft, J.R.]]
[[Category: Luft JR]]
[[Category: Pangborn, W.A.]]
[[Category: Pangborn WA]]
[[Category: DTM]]
[[Category: SO4]]
[[Category: antifolate]]
[[Category: dihydrofolate reductase]]
[[Category: human dhfr]]
[[Category: n9-c10 reverse bridge pyrolopyrimidine]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:15:25 2007''

Latest revision as of 10:49, 14 February 2024

Analysis of Two Polymorphic Forms of a Pyrido[2,3-d]pyrimidine N9-C10 Reverse-Bridge Antifolate Binary Complex with Human Dihydrofolate ReductaseAnalysis of Two Polymorphic Forms of a Pyrido[2,3-d]pyrimidine N9-C10 Reverse-Bridge Antifolate Binary Complex with Human Dihydrofolate Reductase

Structural highlights

1mvs is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.9Å
Ligands:,
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]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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

1mvs, resolution 1.90Å

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