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1rx2

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(New page: 200px<br /><applet load="1rx2" size="450" color="white" frame="true" align="right" spinBox="true" caption="1rx2, resolution 1.8&Aring;" /> '''DIHYDROFOLATE REDUCTA...)
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[[Image:1rx2.jpg|left|200px]]<br /><applet load="1rx2" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1rx2, resolution 1.8&Aring;" />
 
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'''DIHYDROFOLATE REDUCTASE (E.C.1.5.1.3) COMPLEXED WITH WITH FOLATE AND NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE (OXIDIZED FORM)'''<br />
 
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==Overview==
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==DIHYDROFOLATE REDUCTASE (E.C.1.5.1.3) COMPLEXED WITH WITH FOLATE AND NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE (OXIDIZED FORM)==
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The reaction catalyzed by Escherichia coli dihydrofolate reductase, (ecDHFR) cycles through five detectable kinetic intermediates: holoenzyme, Michaelis complex, ternary product complex, tetrahydrofolate (THF) binary, complex, and THF.NADPH complex. Isomorphous crystal structures analogous, to these five intermediates and to the transition state (as represented by, the methotrexate-NADPH complex) have been used to assemble a 2.1 A, resolution movie depicting loop and subdomain movements during the, catalytic cycle (see Supporting Information). The structures suggest that, the M20 loop is predominantly closed over the reactants in the holoenzyme, Michaelis, and transition state complexes. But, during the remainder of, the cycle, when nicotinamide is not bound, the loop occludes (protrudes, into) the nicotinamide-ribose binding pocket. Upon changing from the, closed to the occluded conformation, the central portion of the loop, rearranges from beta-sheet to 3(10) helix. The change may occur by way of, an irregularly structured open loop conformation, which could transiently, admit a water molecule into position to protonate N5 of dihydrofolate., From the Michaelis to the transition state analogue complex, rotation, between two halves of ecDHFR, the adenosine binding subdomain and loop, subdomain, closes the (p-aminobenzoyl)glutamate (pABG) binding crevice by, approximately 0.5 A. Resulting enhancement of contacts with the pABG, moiety may stabilize puckering at C6 of the pteridine ring in the, transition state. The subdomain rotation is further adjusted by, cofactor-induced movements (approximately 0.5 A) of helices B and C, producing a larger pABG cleft in the THF.NADPH analogue complex than in, the THF analogue complex. Such movements may explain how THF release is, assisted by NADPH binding. Subdomain rotation is not observed in, vertebrate DHFR structures, but an analogous loop movement (residues, 59-70) appears to similarly adjust the pABG cleft width, suggesting that, these movements are important for catalysis. Loop movement, also, unobserved in vertebrate DHFR structures, may preferentially weaken NADP+, vs NADPH binding in ecDHFR, an evolutionary adaptation to reduce product, inhibition in the NADP+ rich environment of prokaryotes.
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<StructureSection load='1rx2' size='340' side='right'caption='[[1rx2]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1rx2]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1RX2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1RX2 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=FOL:FOLIC+ACID'>FOL</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1rx2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1rx2 OCA], [https://pdbe.org/1rx2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1rx2 RCSB], [https://www.ebi.ac.uk/pdbsum/1rx2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1rx2 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/DYR_ECOLI DYR_ECOLI] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/rx/1rx2_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=1rx2 ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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1RX2 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with MN, FOL, BME and NAP 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=1RX2 OCA].
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*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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Loop and subdomain movements in the mechanism of Escherichia coli dihydrofolate reductase: crystallographic evidence., Sawaya MR, Kraut J, Biochemistry. 1997 Jan 21;36(3):586-603. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9012674 9012674]
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[[Category: Dihydrofolate reductase]]
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[[Category: Escherichia coli]]
[[Category: Escherichia coli]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Sawaya, M.R.]]
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[[Category: Sawaya MR]]
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[[Category: BME]]
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[[Category: FOL]]
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[[Category: MN]]
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[[Category: NAP]]
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[[Category: methotrexate resistance]]
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[[Category: nadp]]
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[[Category: one-carbon metabolism]]
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[[Category: oxidoreductase]]
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[[Category: trimethoprim resistance]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 01:54:59 2007''
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Current revision

DIHYDROFOLATE REDUCTASE (E.C.1.5.1.3) COMPLEXED WITH WITH FOLATE AND NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE (OXIDIZED FORM)

PDB ID 1rx2

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