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==Unexpected formation of an epoxide-derived multisubstrate adduct inhibitor on the active site of GAR transformylase==
==Unexpected formation of an epoxide-derived multisubstrate adduct inhibitor on the active site of GAR transformylase==
<StructureSection load='1jkx' size='340' side='right' caption='[[1jkx]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
<StructureSection load='1jkx' size='340' side='right'caption='[[1jkx]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1jkx]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_coli"_migula_1895 "bacillus coli" migula 1895]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JKX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1JKX FirstGlance]. <br>
<table><tr><td colspan='2'>[[1jkx]] is a 4 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=1JKX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1JKX FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=138:N-[5-O-PHOSPHONO-RIBOFURANOSYL]-2-[2-HYDROXY-2-[4-[GLUTAMIC+ACID]-N-CARBONYLPHENYL]-3-[2-AMINO-4-HYDROXY-QUINAZOLIN-6-YL]-PROPANYLAMINO]-ACETAMIDE'>138</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6&#8491;</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PURN ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 "Bacillus coli" Migula 1895])</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=138:N-[5-O-PHOSPHONO-RIBOFURANOSYL]-2-[2-HYDROXY-2-[4-[GLUTAMIC+ACID]-N-CARBONYLPHENYL]-3-[2-AMINO-4-HYDROXY-QUINAZOLIN-6-YL]-PROPANYLAMINO]-ACETAMIDE'>138</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1jkx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1jkx OCA], [https://pdbe.org/1jkx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1jkx RCSB], [https://www.ebi.ac.uk/pdbsum/1jkx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1jkx ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1jkx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1jkx OCA], [http://pdbe.org/1jkx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1jkx RCSB], [http://www.ebi.ac.uk/pdbsum/1jkx PDBsum]</span></td></tr>
</table>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PUR3_ECOLI PUR3_ECOLI]
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
Check<jmol>
   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/jk/1jkx_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/jk/1jkx_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
Line 18: Line 20:
</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=1jkx ConSurf].
</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=1jkx ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Multisubstrate adduct inhibitors (MAI) of glycinamide ribonucleotide transformylase (GAR Tfase), which incorporate key features of the folate cofactor and the beta-GAR substrate, typically exhibit K(i)'s in the picomolar range. However, these compounds have reduced bioavailability due to the incorporation of a negatively charged phosphate moiety that prevents effective cellular uptake. Thus, a folate analogue that is capable of adduct formation with the substrate on the enzyme active site could lead to a potent GAR Tfase inhibitor that takes advantage of the cellular folate transport systems. We synthesized a dibromide folate analogue, 10-bromo-10-bromomethyl-5,8,10-trideazafolic acid, that was an intermediate designed to assemble with the substrate beta-GAR on the enzyme active site. We have now determined the crystal structure of the Escherichia coli GAR Tfase/MAI complex at 1.6 A resolution to ascertain the nature and mechanism of its time-dependent inhibition. The high-resolution crystal structure clearly revealed the existence of a covalent adduct between the substrate beta-GAR and the folate analogue (K(i) = 20 microM). However, the electron density map surprisingly indicated a C10 hydroxyl in the adduct rather than a bromide and suggested that the multisubstrate adduct is not formed directly from the dibromide but proceeds via an epoxide. Subsequently, we demonstrated the in situ conversion of the dibromide to the epoxide. Moreover, synthesis of the authentic epoxide confirmed that its inhibitory, time-dependent, and cytotoxic properties are comparable to those of the dibromide. Further, inhibition was strongest when the dibromide or epoxide is preincubated with both enzyme and substrate, indicating that inhibition occurs via the enzyme-dependent formation of the multisubstrate adduct. Thus, the crystal structure revealed the successful formation of an enzyme-assembled multisubstrate adduct and highlighted a potential application for epoxides, and perhaps aziridines, in the design of efficacious GAR Tfase inhibitors.
Unexpected formation of an epoxide-derived multisubstrate adduct inhibitor on the active site of GAR transformylase.,Greasley SE, Marsilje TH, Cai H, Baker S, Benkovic SJ, Boger DL, Wilson IA Biochemistry. 2001 Nov 13;40(45):13538-47. PMID:11695901<ref>PMID:11695901</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1jkx" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Bacillus coli migula 1895]]
[[Category: Escherichia coli]]
[[Category: Phosphoribosylglycinamide formyltransferase]]
[[Category: Large Structures]]
[[Category: Baker, S]]
[[Category: Baker S]]
[[Category: Benkovic, S J]]
[[Category: Benkovic SJ]]
[[Category: Boger, D L]]
[[Category: Boger DL]]
[[Category: Cai, H]]
[[Category: Cai H]]
[[Category: Greasley, S E]]
[[Category: Greasley SE]]
[[Category: Marsilje, T H]]
[[Category: Marsilje TH]]
[[Category: Wilson, I A]]
[[Category: Wilson IA]]
[[Category: Anti-cancer agent]]
[[Category: Enzyme-assembled multisubstrate adduct inhibitor complex]]
[[Category: Purine biosynthesis]]
[[Category: Transferase]]

Latest revision as of 16:24, 13 March 2024

Unexpected formation of an epoxide-derived multisubstrate adduct inhibitor on the active site of GAR transformylaseUnexpected formation of an epoxide-derived multisubstrate adduct inhibitor on the active site of GAR transformylase

Structural highlights

1jkx is a 4 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 1.6Å
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.

1jkx, resolution 1.60Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
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