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[[Image:2ano.gif|left|200px]]


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==Crystal structure of E.coli dihydrofolate reductase in complex with NADPH and the inhibitor MS-SH08-17==
The line below this paragraph, containing "STRUCTURE_2ano", creates the "Structure Box" on the page.
<StructureSection load='2ano' size='340' side='right'caption='[[2ano]], [[Resolution|resolution]] 2.68&Aring;' scene=''>
You may change the PDB parameter (which sets the PDB file loaded into the applet)  
== Structural highlights ==
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
<table><tr><td colspan='2'>[[2ano]] 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=2ANO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ANO FirstGlance]. <br>
or leave the SCENE parameter empty for the default display.
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.68&#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=817:1-{[N-(1-IMINO-GUANIDINO-METHYL)]SULFANYLMETHYL}-3-TRIFLUOROMETHYL-BENZENE'>817</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr>
{{STRUCTURE_2ano| PDB=2ano |  SCENE= }}
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2ano FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ano OCA], [https://pdbe.org/2ano PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ano RCSB], [https://www.ebi.ac.uk/pdbsum/2ano PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ano ProSAT]</span></td></tr>
</table>
== Function ==
[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.
== 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/an/2ano_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=2ano ConSurf].
<div style="clear:both"></div>


'''Crystal structure of E.coli dihydrofolate reductase in complex with NADPH and the inhibitor MS-SH08-17'''
==See Also==
 
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
 
__TOC__
==Overview==
</StructureSection>
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.
 
==About this Structure==
2ANO is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ANO OCA].
 
==Reference==
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://www.ncbi.nlm.nih.gov/pubmed/17125251 17125251]
[[Category: Dihydrofolate reductase]]
[[Category: Escherichia coli]]
[[Category: Escherichia coli]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Brown, E D.]]
[[Category: Brown ED]]
[[Category: Daigle, D M.]]
[[Category: Daigle DM]]
[[Category: Hughes, D W.]]
[[Category: Hughes DW]]
[[Category: Jackson, S G.]]
[[Category: Jackson SG]]
[[Category: Junop, M S.]]
[[Category: Junop MS]]
[[Category: Mayer, S.]]
[[Category: Mayer S]]
[[Category: Organ, M.]]
[[Category: Organ M]]
[[Category: Summerfield, R L.]]
[[Category: Summerfield RL]]
[[Category: Dhfr]]
[[Category: Protein inhibitor complex]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May  3 19:15:40 2008''

Latest revision as of 12:13, 14 February 2024

Crystal structure of E.coli dihydrofolate reductase in complex with NADPH and the inhibitor MS-SH08-17Crystal structure of E.coli dihydrofolate reductase in complex with NADPH and the inhibitor MS-SH08-17

Structural highlights

2ano is a 1 chain structure with sequence from Escherichia coli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.68Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DYR_ECOLI Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.

Evolutionary Conservation

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

See Also

2ano, resolution 2.68Å

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