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1gar

From Proteopedia

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[[Image:1gar.gif|left|200px]]
 
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{{Structure
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==TOWARDS STRUCTURE-BASED DRUG DESIGN: CRYSTAL STRUCTURE OF A MULTISUBSTRATE ADDUCT COMPLEX OF GLYCINAMIDE RIBONUCLEOTIDE TRANSFORMYLASE AT 1.96 ANGSTROMS RESOLUTION==
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|PDB= 1gar |SIZE=350|CAPTION= <scene name='initialview01'>1gar</scene>, resolution 1.96&Aring;
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<StructureSection load='1gar' size='340' side='right'caption='[[1gar]], [[Resolution|resolution]] 1.96&Aring;' scene=''>
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|SITE=
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=U89:N-[4-[[3-(2,4-DIAMINO-1,6-DIHYDRO-6-OXO-4-PYRIMIDINYL)-PROPYL]-[2-((2-OXO-2-((4-PHOSPHORIBOXY)-BUTYL)-AMINO)-ETHYL)-THIO-ACETYL]-AMINO]BENZOYL]-1-GLUTAMIC+ACID'>U89</scene>
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<table><tr><td colspan='2'>[[1gar]] 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=1GAR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GAR FirstGlance]. <br>
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|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>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.96&#8491;</td></tr>
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|GENE=
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=U89:N-[4-[[3-(2,4-DIAMINO-1,6-DIHYDRO-6-OXO-4-PYRIMIDINYL)-PROPYL]-[2-((2-OXO-2-((4-PHOSPHORIBOXY)-BUTYL)-AMINO)-ETHYL)-THIO-ACETYL]-AMINO]BENZOYL]-1-GLUTAMIC+ACID'>U89</scene></td></tr>
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|DOMAIN=
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1gar FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gar OCA], [https://pdbe.org/1gar PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1gar RCSB], [https://www.ebi.ac.uk/pdbsum/1gar PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1gar ProSAT]</span></td></tr>
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|RELATEDENTRY=
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</table>
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1gar FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gar OCA], [http://www.ebi.ac.uk/pdbsum/1gar PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1gar RCSB]</span>
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== Function ==
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}}
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[https://www.uniprot.org/uniprot/PUR3_ECOLI PUR3_ECOLI]
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== Evolutionary Conservation ==
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'''TOWARDS STRUCTURE-BASED DRUG DESIGN: CRYSTAL STRUCTURE OF A MULTISUBSTRATE ADDUCT COMPLEX OF GLYCINAMIDE RIBONUCLEOTIDE TRANSFORMYLASE AT 1.96 ANGSTROMS RESOLUTION'''
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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==Overview==
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ga/1gar_consurf.spt"</scriptWhenChecked>
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An inhibitor complex structure of glycinamide ribonucleotide transformylase (GAR-Tfase; EC 2.1.2.2) from Escherichia coli has been determined with a multisubstrate adduct BW1476U89 to an R-value of 19.1% at 1.96 A resolution. The structure was determined by a combination of molecular and single isomorphous replacement using data from two different monoclinic crystal lattices and collecting data from crystals soaked in 20% (w/v) methyl-pentanediol as cryoprotectant for shock-freezing at -150 degrees C. The multisubstrate adduct is bound in an extended crevice at the interface between the two functional domains of the enzyme. This inhibitor is positioned in the binding site by three sets of tight interactions with its phosphate, glutamate and pyrimidone ring moieties, while its interventing linker atoms are more flexible and adopt two distinct sets of conformations. The highly conserved Arg103, His108 and Gln170 residues that are key in ligand binding and catalysis (His108), have compensatory conformational variation that gives some clues as to their role in substrate specificity and in the formyl transfer. The molecular design of 1476U89 as a multisubstrate adduct inhibitor (Ki approximately 100 pM at pH 8.5), is confirmed as it closely mimics the shape, molecular interaction and combined binding constants of the natural 10-formyltetrahydrofolate (10-CHO-H4F; Km approximately 77.4 microM at pH 8.5) and glycinamide-ribonucleotide (GAR; Km approximately 8.1 microM at pH 8.5) substrates. The stereochemistry of this ligand complex suggests that His108 may act as an electrophile stabilizing the oxyanion of the tetrahedral intermediate that is formed as a result of the direct attack on the 10-CHO-H4F by the amino group of GAR. Structural comparison of the folate binding modes among GAR-Tfase, dihydrofolate reductase and thymidylate synthase reveals that folate derivates bound to GAR-Tfase differentially adopt the trans conformation for the dihedral angle between atoms C-6 and C-9 providing a handle for targeting specific folate-dependent enzymes. The structural information derived from two different discrete conformations of the ligand in the binding site also suggests several leads for the de novo design of inhibitors of GAR-Tfase that may develop into useful chemotherapeutic agents.
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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==About this Structure==
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</jmolCheckbox>
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1GAR 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=1GAR OCA].
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</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=1gar ConSurf].
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<div style="clear:both"></div>
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==Reference==
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__TOC__
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Towards structure-based drug design: crystal structure of a multisubstrate adduct complex of glycinamide ribonucleotide transformylase at 1.96 A resolution., Klein C, Chen P, Arevalo JH, Stura EA, Marolewski A, Warren MS, Benkovic SJ, Wilson IA, J Mol Biol. 1995 May 26;249(1):153-75. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/7776369 7776369]
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</StructureSection>
[[Category: Escherichia coli]]
[[Category: Escherichia coli]]
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[[Category: Phosphoribosylglycinamide formyltransferase]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Arevalo JH]]
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[[Category: Arevalo, J H.]]
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[[Category: Chen P]]
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[[Category: Chen, P.]]
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[[Category: Klein C]]
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[[Category: Klein, C.]]
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[[Category: Wilson IA]]
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[[Category: Wilson, I A.]]
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[[Category: transferase (formyl)]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 20:40:15 2008''
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Current revision

TOWARDS STRUCTURE-BASED DRUG DESIGN: CRYSTAL STRUCTURE OF A MULTISUBSTRATE ADDUCT COMPLEX OF GLYCINAMIDE RIBONUCLEOTIDE TRANSFORMYLASE AT 1.96 ANGSTROMS RESOLUTION

PDB ID 1gar

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