1c2t: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==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.== | ||
<StructureSection load='1c2t' size='340' side='right' caption='[[1c2t]], [[Resolution|resolution]] 2.10Å' scene=''> | <StructureSection load='1c2t' size='340' side='right' caption='[[1c2t]], [[Resolution|resolution]] 2.10Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[1c2t]] is a 2 chain structure | <table><tr><td colspan='2'>[[1c2t]] is a 2 chain structure. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1C2T FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GAR:GLYCINAMIDE+RIBONUCLEOTIDE'>GAR</scene>, <scene name='pdbligand=NHS:10-FORMYL-5,8,10-TRIDEAZAFOLIC+ACID'>NHS</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GAR:GLYCINAMIDE+RIBONUCLEOTIDE'>GAR</scene>, <scene name='pdbligand=NHS:10-FORMYL-5,8,10-TRIDEAZAFOLIC+ACID'>NHS</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1c3e|1c3e]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1c3e|1c3e]]</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='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'>[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://pdbe.org/1c2t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1c2t RCSB], [http://www.ebi.ac.uk/pdbsum/1c2t PDBsum]</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=1c2t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1c2t OCA], [http://pdbe.org/1c2t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1c2t RCSB], [http://www.ebi.ac.uk/pdbsum/1c2t PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1c2t ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
| Line 16: | Line 17: | ||
<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
</jmolCheckbox> | </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/ | </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> | <div style="clear:both"></div> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
| Line 31: | Line 32: | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Phosphoribosylglycinamide formyltransferase]] | [[Category: Phosphoribosylglycinamide formyltransferase]] | ||
[[Category: Benkovic, S J]] | [[Category: Benkovic, S J]] | ||
Revision as of 14:06, 24 August 2017
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
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe 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. 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:10606510[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||||