1ex8

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(New page: 200px<br /><applet load="1ex8" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ex8, resolution 1.85&Aring;" /> '''CRYSTAL STRUCTURE OF...)
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[[Image:1ex8.gif|left|200px]]<br /><applet load="1ex8" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1ex8, resolution 1.85&Aring;" />
 
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'''CRYSTAL STRUCTURE OF 6-HYDROXYMETHYL-7,8-DIHYDROPTERIN PYROPHOSPHOKINASE COMPLEXED WITH HP4A, THE TWO-SUBSTRATE-MIMICKING INHIBITOR'''<br />
 
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==Overview==
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==CRYSTAL STRUCTURE OF 6-HYDROXYMETHYL-7,8-DIHYDROPTERIN PYROPHOSPHOKINASE COMPLEXED WITH HP4A, THE TWO-SUBSTRATE-MIMICKING INHIBITOR==
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6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) catalyzes the, transfer of pyrophosphate from ATP to 6-hydroxymethyl-7,8-dihydropterin, (HP), leading to the biosynthesis of folate cofactors. Like other enzymes, in the folate pathway, HPPK is an ideal target for the development of, antimicrobial agents because the enzyme is essential for microorganisms, but is absent from human and animals. Three bisubstrate analogues have, been synthesized for HPPK and characterized by biochemical and X-ray, crystallographic analyses. All three bisubstrate analogues consist of a, pterin, an adenosine moiety, and a link composed of 2-4 phosphoryl groups., P(1)-(6-Hydroxymethylpterin)-P(2)-(5'-adenosyl)diphosphate (HP(2)A, 5), shows little affinity and inhibitory activity for E. coli HPPK., P(1)-(6-Hydroxymethylpterin)-P(3)-(5'-adenosyl)triphosphate (HP(3)A, 6), shows moderate affinity and inhibitory activity with K(d) = 4.25 microM in, the presence of Mg(2+) and IC(50) = 1.27 microM., P(1)-(6-Hydroxymethylpterin)-P(4)-(5'-adenosyl)tetraphosphate (HP(4)A, 7), shows the highest affinity and inhibitory activity with K(d) = 0.47 microM, in the presence of Mg(2+) and IC(50) = 0.44 microM. The affinity of, MgHP(4)A for HPPK is approximately 116 and 76 times higher than that of, MgADP and 6-hydroxymethylpterin, respectively. The crystal structure of, HPPK in complex with 7 (HPPK.MgHP(4)A) has been determined at 1.85 A, resolution with a crystallographic R factor of 0.185. The crystal, structure shows that 7 occupies both HP- and ATP-binding sites and induces, significant conformational changes in HPPK. The biochemical and structural, studies of the bisubstrate analogues indicate that the bisubstrate, analogue approach can produce more potent inhibitors for HPPK and the, minimum length of the link for a bisubstrate analogue is approximately 7, A.
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<StructureSection load='1ex8' size='340' side='right'caption='[[1ex8]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1ex8]] is a 1 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=1EX8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1EX8 FirstGlance]. <br>
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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]] 1.85&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A4P:6-(ADENOSINE+TETRAPHOSPHATE-METHYL)-7,8-DIHYDROPTERIN'>A4P</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
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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=1ex8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ex8 OCA], [https://pdbe.org/1ex8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ex8 RCSB], [https://www.ebi.ac.uk/pdbsum/1ex8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ex8 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/HPPK_ECOLI HPPK_ECOLI]
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== Evolutionary Conservation ==
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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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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ex/1ex8_consurf.spt"</scriptWhenChecked>
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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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</jmolCheckbox>
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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=1ex8 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) catalyzes the transfer of pyrophosphate from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP), leading to the biosynthesis of folate cofactors. Like other enzymes in the folate pathway, HPPK is an ideal target for the development of antimicrobial agents because the enzyme is essential for microorganisms but is absent from human and animals. Three bisubstrate analogues have been synthesized for HPPK and characterized by biochemical and X-ray crystallographic analyses. All three bisubstrate analogues consist of a pterin, an adenosine moiety, and a link composed of 2-4 phosphoryl groups. P(1)-(6-Hydroxymethylpterin)-P(2)-(5'-adenosyl)diphosphate (HP(2)A, 5) shows little affinity and inhibitory activity for E. coli HPPK. P(1)-(6-Hydroxymethylpterin)-P(3)-(5'-adenosyl)triphosphate (HP(3)A, 6) shows moderate affinity and inhibitory activity with K(d) = 4.25 microM in the presence of Mg(2+) and IC(50) = 1.27 microM. P(1)-(6-Hydroxymethylpterin)-P(4)-(5'-adenosyl)tetraphosphate (HP(4)A, 7) shows the highest affinity and inhibitory activity with K(d) = 0.47 microM in the presence of Mg(2+) and IC(50) = 0.44 microM. The affinity of MgHP(4)A for HPPK is approximately 116 and 76 times higher than that of MgADP and 6-hydroxymethylpterin, respectively. The crystal structure of HPPK in complex with 7 (HPPK.MgHP(4)A) has been determined at 1.85 A resolution with a crystallographic R factor of 0.185. The crystal structure shows that 7 occupies both HP- and ATP-binding sites and induces significant conformational changes in HPPK. The biochemical and structural studies of the bisubstrate analogues indicate that the bisubstrate analogue approach can produce more potent inhibitors for HPPK and the minimum length of the link for a bisubstrate analogue is approximately 7 A.
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==About this Structure==
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Bisubstrate analogue inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: synthesis and biochemical and crystallographic studies.,Shi G, Blaszczyk J, Ji X, Yan H J Med Chem. 2001 Apr 26;44(9):1364-71. PMID:11311059<ref>PMID:11311059</ref>
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1EX8 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 MG, CL and A4P as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/2-amino-4-hydroxy-6-hydroxymethyldihydropteridine_diphosphokinase 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.6.3 2.7.6.3] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1EX8 OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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Bisubstrate analogue inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: synthesis and biochemical and crystallographic studies., Shi G, Blaszczyk J, Ji X, Yan H, J Med Chem. 2001 Apr 26;44(9):1364-71. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11311059 11311059]
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</div>
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[[Category: 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase]]
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<div class="pdbe-citations 1ex8" style="background-color:#fffaf0;"></div>
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[[Category: Escherichia coli]]
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[[Category: Single protein]]
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[[Category: Blaszczyk, J.]]
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[[Category: Ji, X.]]
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[[Category: A4P]]
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[[Category: CL]]
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[[Category: MG]]
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[[Category: active-site architecture]]
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[[Category: antimicrobial agent]]
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[[Category: atp]]
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[[Category: bisubstrate-mimicking inhibitor]]
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[[Category: drug design]]
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[[Category: folate]]
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[[Category: hppk]]
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[[Category: pterin]]
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[[Category: pyrophosphokinase]]
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[[Category: pyrophosphoryl transfer]]
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[[Category: substrate specificity]]
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[[Category: x-ray crystallography]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 14:23:42 2007''
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==See Also==
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*[[HPPK 3D structures|HPPK 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Escherichia coli]]
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[[Category: Large Structures]]
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[[Category: Blaszczyk J]]
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[[Category: Ji X]]

Current revision

CRYSTAL STRUCTURE OF 6-HYDROXYMETHYL-7,8-DIHYDROPTERIN PYROPHOSPHOKINASE COMPLEXED WITH HP4A, THE TWO-SUBSTRATE-MIMICKING INHIBITOR

PDB ID 1ex8

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