1c3e: Difference between revisions

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New page: left|200px<br /><applet load="1c3e" size="450" color="white" frame="true" align="right" spinBox="true" caption="1c3e, resolution 2.10Å" /> '''NEW INSIGHTS INTO IN...
 
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[[Image:1c3e.gif|left|200px]]<br /><applet load="1c3e" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1c3e, resolution 2.10&Aring;" />
'''NEW INSIGHTS INTO INHIBITOR DESIGN FROM THE CRYSTAL STRUCTURE AND NMR STUDIES OF E. COLI GAR TRANSFORMYLATE IN COMPLEX WITH BETA-GAR AND 10-FORMYL-5,8,10-TRIDEAZAFOLIC ACID.'''<br />


==Overview==
==NEW INSIGHTS INTO INHIBITOR DESIGN FROM THE CRYSTAL STRUCTURE AND NMR STUDIES OF E. COLI GAR TRANSFORMYLATE IN COMPLEX WITH BETA-GAR AND 10-FORMYL-5,8,10-TRIDEAZAFOLIC ACID.==
The crystal structure of Escherichia coli GAR Tfase at 2.1 A resolution in, complex with 10-formyl-5,8,10-trideazafolic acid (10-formyl-TDAF, K(i) =, 260 nM), an inhibitor designed to form an enzyme-assembled multisubstrate, adduct with the substrate, beta-GAR, was studied to determine the exact, nature of its inhibitory properties. Rather than forming the expected, covalent adduct, the folate inhibitor binds as the hydrated aldehyde, (gem-diol) in the enzyme active site, in a manner that mimics the, tetrahedral intermediate of the formyl transfer reaction. In this hydrated, form, the inhibitor not only provides unexpected insights into the, catalytic mechanism but also explains the 10-fold difference in inhibitor, potency between 10-formyl-TDAF and the corresponding alcohol, and a, further 10-fold difference for inhibitors that lack the alcohol. The, presence of the hydrated aldehyde was confirmed in solution by (13)C-(1)H, NMR spectroscopy of the ternary GAR Tfase-beta-GAR-10-formyl-TDAF complex, using the (13)C-labeled 10-formyl-TDAF. This insight into the behavior of, the inhibitor, which is analogous to protease or transaminase inhibitors, provides a novel and previously unrecognized basis for the design of more, potent inhibitors of the folate-dependent formyl transfer enzymes of the, purine biosynthetic pathway and development of anti-neoplastic agents.
<StructureSection load='1c3e' size='340' side='right'caption='[[1c3e]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 
== Structural highlights ==
==About this Structure==
<table><tr><td colspan='2'>[[1c3e]] is a 2 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=1C3E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1C3E FirstGlance]. <br>
1C3E 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 NHR and GAR as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Phosphoribosylglycinamide_formyltransferase Phosphoribosylglycinamide formyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.2.2 2.1.2.2] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1C3E OCA].
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
 
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GAR:GLYCINAMIDE+RIBONUCLEOTIDE'>GAR</scene>, <scene name='pdbligand=NHR:2-{4-[2-(2-AMINO-4-HYDROXY-QUINAZOLIN-6-YL)-1-CARBOXY-ETHYL]-BENZOYLAMINO}-PENTANEDIOIC+ACID'>NHR</scene></td></tr>
==Reference==
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1c3e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1c3e OCA], [https://pdbe.org/1c3e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1c3e RCSB], [https://www.ebi.ac.uk/pdbsum/1c3e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1c3e ProSAT]</span></td></tr>
New insights into inhibitor design from the crystal structure and NMR studies of Escherichia coli GAR transformylase in complex with beta-GAR and 10-formyl-5,8,10-trideazafolic acid., Greasley SE, Yamashita MM, Cai H, Benkovic SJ, Boger DL, Wilson IA, Biochemistry. 1999 Dec 21;38(51):16783-93. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10606510 10606510]
</table>
== Function ==
[https://www.uniprot.org/uniprot/PUR3_ECOLI PUR3_ECOLI]  
== 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/c3/1c3e_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=1c3e ConSurf].
<div style="clear:both"></div>
__TOC__
</StructureSection>
[[Category: Escherichia coli]]
[[Category: Escherichia coli]]
[[Category: Phosphoribosylglycinamide formyltransferase]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Benkovic SJ]]
[[Category: Benkovic, S.J.]]
[[Category: Boger DL]]
[[Category: Boger, D.L.]]
[[Category: Cai H]]
[[Category: Cai, H.]]
[[Category: Greasley SE]]
[[Category: Greasley, S.E.]]
[[Category: Wilson IA]]
[[Category: Wilson, I.A.]]
[[Category: Yamashita MM]]
[[Category: Yamashita, M.M.]]
[[Category: GAR]]
[[Category: NHR]]
[[Category: anti-cancer agent]]
[[Category: inhibitor complex]]
[[Category: purine biosynthesis]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 12:07:46 2007''

Latest revision as of 09:40, 7 February 2024

NEW INSIGHTS INTO INHIBITOR DESIGN FROM THE CRYSTAL STRUCTURE AND NMR STUDIES OF E. COLI GAR TRANSFORMYLATE IN COMPLEX WITH BETA-GAR AND 10-FORMYL-5,8,10-TRIDEAZAFOLIC ACID.NEW INSIGHTS INTO INHIBITOR DESIGN FROM THE CRYSTAL STRUCTURE AND NMR STUDIES OF E. COLI GAR TRANSFORMYLATE IN COMPLEX WITH BETA-GAR AND 10-FORMYL-5,8,10-TRIDEAZAFOLIC ACID.

Structural highlights

1c3e is a 2 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 2.1Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PUR3_ECOLI

Evolutionary Conservation

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

1c3e, resolution 2.10Å

Drag the structure with the mouse to rotate

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