2anq

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[[Image:2anq.gif|left|200px]]<br /><applet load="2anq" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="2anq, resolution 2.130&Aring;" />
 
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'''Crystal Structure of E.coli DHFR in complex with NADPH and the inhibitor compound 10a.'''<br />
 
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==Overview==
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==Crystal Structure of E.coli DHFR in complex with NADPH and the inhibitor compound 10a.==
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Dihydrofolate reductase (DHFR) is a vital metabolic enzyme and thus a clinically prominent target in the design of antimetabolites. In this work, we identify 1,4-bis-{[N-(1-imino-1-guanidino-methyl)]sulfanylmethyl}-3,6-dimethyl-benz ene (compound 1) as the correct structure of the previously reported DHFR inhibitor 1,4-bis-{(iminothioureidomethyl)aminomethyl}-3,6-dimethyl-benzene (compound 2). The fact that compound 1 has an uncharacteristic structure for DHFR inhibitors, and an affinity (KI of 11.5 nM) comparable to potent inhibitors such as methotrexate and trimethoprim, made this inhibitor of interest for further analysis. We have conducted a characterization of the primary interactions of compound 1 and DHFR using a combination of X-ray structure and SAR analysis. The crystal structure of E. coli DHFR in complex with compound 1 and NADPH reveals that one portion of this inhibitor exploits a unique binding surface, the M20 loop. The importance of this interface was further confirmed by SAR analysis and additional structural characterization.
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<StructureSection load='2anq' size='340' side='right'caption='[[2anq]], [[Resolution|resolution]] 2.13&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2anq]] 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=2ANQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ANQ 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]] 2.13&#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=C1A:(2,5-DIMETHYLBENZENE-1,4-DIYL)DIMETHANEDIYL+BIS(N-CARBAMIMIDOYLCARBAMIMIDOTHIOATE)'>C1A</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</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=2anq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2anq OCA], [https://pdbe.org/2anq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2anq RCSB], [https://www.ebi.ac.uk/pdbsum/2anq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2anq 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/an/2anq_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=2anq 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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2ANQ 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 <scene name='pdbligand=MN:'>MN</scene>, <scene name='pdbligand=NAP:'>NAP</scene> and <scene name='pdbligand=C1A:'>C1A</scene> 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://oca.weizmann.ac.il/oca-bin/ocashort?id=2ANQ 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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A 2.13 A structure of E. coli dihydrofolate reductase bound to a novel competitive inhibitor reveals a new binding surface involving the M20 loop region., Summerfield RL, Daigle DM, Mayer S, Mallik D, Hughes DW, Jackson SG, Sulek M, Organ MG, Brown ED, Junop MS, J Med Chem. 2006 Nov 30;49(24):6977-86. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17125251 17125251]
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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: Brown, E D.]]
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[[Category: Brown ED]]
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[[Category: Daigle, D M.]]
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[[Category: Daigle DM]]
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[[Category: Hughes, D W.]]
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[[Category: Hughes DW]]
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[[Category: Jackson, S G.]]
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[[Category: Jackson SG]]
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[[Category: Junop, M S.]]
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[[Category: Junop MS]]
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[[Category: Mayer, S.]]
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[[Category: Mayer S]]
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[[Category: Organ, M.]]
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[[Category: Organ M]]
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[[Category: Summerfield, R L.]]
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[[Category: Summerfield RL]]
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[[Category: C1A]]
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[[Category: MN]]
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[[Category: NAP]]
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[[Category: dhfr]]
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[[Category: protein inhibitor complex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:29:10 2008''
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Current revision

Crystal Structure of E.coli DHFR in complex with NADPH and the inhibitor compound 10a.

PDB ID 2anq

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