1ex8
From Proteopedia
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| - | [[Image:1ex8.gif|left|200px]] | + | [[Image:1ex8.gif|left|200px]] |
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| - | '''CRYSTAL STRUCTURE OF 6-HYDROXYMETHYL-7,8-DIHYDROPTERIN PYROPHOSPHOKINASE COMPLEXED WITH HP4A, THE TWO-SUBSTRATE-MIMICKING INHIBITOR''' | + | {{Structure |
| + | |PDB= 1ex8 |SIZE=350|CAPTION= <scene name='initialview01'>1ex8</scene>, resolution 1.85Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene> and <scene name='pdbligand=A4P:6-(ADENOSINE TETRAPHOSPHATE-METHYL)-7,8-DIHYDROPTERIN'>A4P</scene> | ||
| + | |ACTIVITY= [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] | ||
| + | |GENE= | ||
| + | }} | ||
| + | |||
| + | '''CRYSTAL STRUCTURE OF 6-HYDROXYMETHYL-7,8-DIHYDROPTERIN PYROPHOSPHOKINASE COMPLEXED WITH HP4A, THE TWO-SUBSTRATE-MIMICKING INHIBITOR''' | ||
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==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1EX8 is a [ | + | 1EX8 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=1EX8 OCA]. |
==Reference== | ==Reference== | ||
| - | 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:// | + | 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://www.ncbi.nlm.nih.gov/pubmed/11311059 11311059] |
[[Category: 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase]] | [[Category: 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase]] | ||
[[Category: Escherichia coli]] | [[Category: Escherichia coli]] | ||
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[[Category: x-ray crystallography]] | [[Category: x-ray crystallography]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 11:01:27 2008'' |
Revision as of 09:01, 20 March 2008
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| , resolution 1.85Å | |||||||
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| Ligands: | , and | ||||||
| Activity: | 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase, with EC number 2.7.6.3 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
CRYSTAL STRUCTURE OF 6-HYDROXYMETHYL-7,8-DIHYDROPTERIN PYROPHOSPHOKINASE COMPLEXED WITH HP4A, THE TWO-SUBSTRATE-MIMICKING INHIBITOR
Overview
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.
About this Structure
1EX8 is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.
Reference
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
Page seeded by OCA on Thu Mar 20 11:01:27 2008
Categories: 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase | Escherichia coli | Single protein | Blaszczyk, J. | Ji, X. | A4P | CL | MG | Active-site architecture | Antimicrobial agent | Atp | Bisubstrate-mimicking inhibitor | Drug design | Folate | Hppk | Pterin | Pyrophosphokinase | Pyrophosphoryl transfer | Substrate specificity | X-ray crystallography
