1c2t: Difference between revisions

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[[Image:1c2t.jpg|left|200px]]


{{Structure
==NEW INSIGHTS INTO INHIBITOR DESIGN FROM THE CRYSTAL STRUCTURE AND NMR STUDIES OF E. COLI GAR TRANSFORMYLASE IN COMPLEX WITH BETA-GAR AND 10-FORMYL-5,8,10-TRIDEAZAFOLIC ACID.==
|PDB= 1c2t |SIZE=350|CAPTION= <scene name='initialview01'>1c2t</scene>, resolution 2.10&Aring;
<StructureSection load='1c2t' size='340' side='right'caption='[[1c2t]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
|SITE=  
== Structural highlights ==
|LIGAND= <scene name='pdbligand=GAR:GLYCINAMIDE+RIBONUCLEOTIDE'>GAR</scene>, <scene name='pdbligand=NHS:10-FORMYL-5,8,10-TRIDEAZAFOLIC+ACID'>NHS</scene>
<table><tr><td colspan='2'>[[1c2t]] 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=1C2T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1C2T FirstGlance]. <br>
|ACTIVITY= <span class='plainlinks'>[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] </span>
</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>
|GENE=
<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=NHS:10-FORMYL-5,8,10-TRIDEAZAFOLIC+ACID'>NHS</scene></td></tr>
|DOMAIN=
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1c2t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1c2t OCA], [https://pdbe.org/1c2t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1c2t RCSB], [https://www.ebi.ac.uk/pdbsum/1c2t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1c2t ProSAT]</span></td></tr>
|RELATEDENTRY=[[1c3e|1C3E]]
</table>
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1c2t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1c2t OCA], [http://www.ebi.ac.uk/pdbsum/1c2t PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1c2t RCSB]</span>
== Function ==
}}
[https://www.uniprot.org/uniprot/PUR3_ECOLI PUR3_ECOLI]
 
== Evolutionary Conservation ==
'''NEW INSIGHTS INTO INHIBITOR DESIGN FROM THE CRYSTAL STRUCTURE AND NMR STUDIES OF E. COLI GAR TRANSFORMYLASE IN COMPLEX WITH BETA-GAR AND 10-FORMYL-5,8,10-TRIDEAZAFOLIC ACID.'''
[[Image:Consurf_key_small.gif|200px|right]]
 
Check<jmol>
 
  <jmolCheckbox>
==Overview==
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/c2/1c2t_consurf.spt"</scriptWhenChecked>
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.
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
 
    <text>to colour the structure by Evolutionary Conservation</text>
==About this Structure==
  </jmolCheckbox>
1C2T 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=1C2T OCA].  
</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=1c2t ConSurf].
 
<div style="clear:both"></div>
==Reference==
__TOC__
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://www.ncbi.nlm.nih.gov/pubmed/10606510 10606510]
</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: anti-cancer agent]]
[[Category: inhibitor complex]]
[[Category: purine biosynthesis]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 19:13:27 2008''

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 TRANSFORMYLASE 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 TRANSFORMYLASE IN COMPLEX WITH BETA-GAR AND 10-FORMYL-5,8,10-TRIDEAZAFOLIC ACID.

Structural highlights

1c2t 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.

1c2t, resolution 2.10Å

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