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2.7.6.3: 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase

This is an abbreviated version!
For detailed information about 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase, go to the full flat file.

Word Map on EC 2.7.6.3

Reaction

ATP
+
6-hydroxymethyl-7,8-dihydropterin
=
AMP
 +
6-hydroxymethyl-7,8-dihydropterin diphosphate

Synonyms

2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase, 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase, 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase/dihydropteroate synthase, 6-hydroxy-7,8-dihydropterin pyrophosphokinase, 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase, 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase-dihydropteroate synthase, 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase/dihydropteroate synthase, 6-hydroxymethyl-7,8-dihydroxypterin pyrophosphokinase/7,8-dihydropteroate synthase, 6-hydroxymethylpterin pyrophosphokinase, 7,8-dihydro-6-hydroxymethylpterin pyrophosphokinase, 7,8-dihydropteroate-synthesizing enzyme, 7,8-dihydroxymethylpterin-pyrophosphokinase, ATP:2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine 6'-pyrophosphotransferase, cytHPPK/DHPS, dihydropterin pyrophosphokinase, FOLK, FtHPPK-DHPS, H2-pteridine-CH2-OH pyrophosphokinase, H2-pteridine-CH2OH pyrophosphokinase, HPPK, HPPK-DHPS, HPPK/DHPS, HPPK/dihydropteroate synthase, hydroxymethyl-7,8-dihydropterin pyrophosphokinase/7,8-dihydropteroate synthase, hydroxymethyldihydropteridine pyrophosphokinase, hydroxymethyldihydropterin diphosphokinase/dihydropteroate synthase, hydroxymethyldihydropterin pyrophosphokinase (HPPK), hydroxymethyldihydropterin pyrophosphokinase-dihydropteroate synthase, mitHPPK/DHPS, More, PPPK, PPPK-DHPS, PVX_123230, pyrophosphokinase, 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine

ECTree

     2 Transferases
         2.7 Transferring phosphorus-containing groups
             2.7.6 Diphosphotransferases
                2.7.6.3 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase

Crystallization

Crystallization on EC 2.7.6.3 - 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase

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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
apo W89A and its ternary complex with Mg-alpha,beta-methyleneadenosine triphosphate and 6-hydroxymethyl-7,8-dihydropterin are crystallized at 19°C using the hanging-drop vapor-diffusion technique. The structure of the ternary complex is determined at 1.25 A resolution
complexed with inhibitor 2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridine-6-carboxylic acid (2-[2-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethanesulfonyl]-ethylcarbamoyl]-ethyl)-amide, sitting drop vapor diffusion method, using 25% (w/v) PEG 3350 and 0.2 M NaCl in 0.1 M HEPES, pH 7.5
hanging-drop vapor-diffusion method. At 0.89-A resolution, two distinct conformations are observed for each of the two residues in the crystal structure of the wild-type enzyme in complex with two 6-hydroxymethyl-7,8-dihydropterin variants, two Mg2+ ions, and an ATP analogue. 1. Complex of wild-type enzyme with 6-hydroxymethylpterin, 6-carboxypterin and alpha,beta-methyleneadenosine 5'-triphosphate, 2. complex of mutant enzyme R82A with 6-hydroxymethyl-7,8-dihydropterin and alpha,beta-methyleneadenosine 5'-triphosphate, 3. complex of mutant enzyme R92A with 6-hydroxymethyl-7,8-dihydropterin and alpha,beta-methyleneadenosine 5'-triphosphate, 4. matant apoenzyme of R82A, 5. mutant apoenzyme of R92A, 6. mutant enzyme R92A in complex with Mg2+
in complex with 2-amino-6-[(2-{4-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2-ylmethylsulfanyl]-piperidin-1-yl}-ethylamino)-methyl]-3H-pteridin-4-one, 2-amino-6-[(2-{4-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2-ylmethylsulfanyl]-piperidin-1-yl}-ethylamino)-methyl]-7,7-dimethyl-7,8-dihydro-3H pteridin-4-one, or 2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydro-pteridine-6-carboxylic acid (2-{4-[5-(6-amino-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethylsulfanyl]-piperidin-1-yl}-ethyl)-amide, sitting drop vapor diffusion method, using 20% or 25% (w/v) PEG 3350 as precipitant, at 19°C
in complex with inhibitors (2R,4R)-1-(2-(2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridine-6-carboxamido)ethyl)-4-((((2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)thio) piperidine-2-carboxylic acid and (2R,4R)-1-(2-(2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridine-6-carboxamido)ethyl)-4-((((2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)sulfonyl) piperidine-2-carboxylic acid
molecular dynamics simulations to investigate the loop dynamics in the binary HPPK-MgATP complex. With loop 3 closed, multiple conformations of loop 2, including the open, semiopen, and closed forms, are all accessible to the binary complex. Loop 3 is unlikely to be opened due to the blockage caused by the binding of ATP
purified recombinant detagged enzyme in complex with different inhibitors and AMPCPP, sitting-drop vapor diffusion method, mixing of 2.2 mg/ml protein in 20 mM Tris-HCl buffer, pH 8.0, 100 mM NaCl, with reservoir solution containing 20% w/v PEG 4000, 0.1 M TrisCl, and 0.172 M CaCl2, or 0.1 M HEPES-NaOH, pH 7.5, 0.2 M CaCl2, and 25-30% PEG 4000, 16-20°C, addition of 2 mM MgCl2, 1 mM AMPCPP, and 1 mM of inhibitor, X-ray diffraction structure determination and analysis, molecular replacement
structure-based model upon ligand binding, molecular dynamics simulation. HPPK can switch to the activated holo state upon the ordered binding of ligands ATP and HP. The ligand-free HPPK can execute large-scale conformational fluctuations around the apo and open basins. ATP prefers to bind to the open conformations and promotes the population of the open state. Only when both ligands are bound, the conformational transitions among all of the three native states can emerge. Higher temperatures promote population shift, while the induced fit pathway is always the predominant activation route of the HPPK system
V83Gdel84-89 and its complex with alpha,beta--methyleneadenosine triphosphate and 6-hydroxymethyl-7,8-dihydropterin are crystallized at 19°C using the hanging-drop vapor-diffusion technique
apoenzyme and in complex with substrate 6-hydroxymethyl-7,8-dihydropteridine or 2-(7-amino-1-methyl-4,5-dioxo-1,4,5,6-tetrahydorpyrimido[4,5-c]pyridazin-3-yl)propanoic acid, sitting drop vapor diffusion method, using 90 mM Tris (pH 8.0), 190 mM sodium acetate, 24% (w/v) polyethylene glycol (PEG) 4000, and 17% (v/v) glycerol, at 18°C
purified enzyme in complex with inhibitor HP-26, sitting drop vapour diffusion method, mixing of 300 nl 11 mg/ml protein in 25 mM HEPES, pH 7.5, 150 mM NaCl, 10% glycerol, 2 mM TCEP, and saturated HP-26, with 300 nl well solution containing 28% w/v poly(ethylene glycol) monomethyl ether 2000, and 100 mM Bis-Tris, pH 6.5, X-ray diffraction structure determination and analysis at 1.7 A resolution
a complex of the purified protein with a substrate analog is crystallized and its structure is solved by multiple anomalous dispersion using phase information obtained from a single crystal of selenomethionine-labeled protein
-
structures of the enzyme from wild-type and sulfa-resistant mutants, both as apoenzyme and as complexes with pteroate and sulfa derivatives. Pteroate stays in active sites without steric constraint. In contrast, parts of the sulfa compounds situated outside of the substrate envelope are in the vicinity of the resistance mutations. Steric conflict between compound and mutant residue along with increased flexibility of loop D2 in the mutants can account for the reduced compound binding affinity to the mutants
crystal structure of HPPk-DHPS in complex with four substrates/analogs. Sulfadoxine's effect on HPPK-DHPS is due to 4-amino benzoic acid mimicry, and resistance mutations surrounding the 4-amino benzoic acid-binding site are present within loop 2 (S382/F/A/Cand A383G), loop 5 (Lys512), loop 6 (Ala553), and 7' helix in loop7 (Val585)
structure of HPPk-DHPS in complex with four substrates/analogs.
crystallization of a complex of the purified bifunctional polypeptide with a pterin monophosphate substrate analogue, structure solved by molecular replacement and refined to 2.3 A resolution. Three-dimensional structure in complex with the oxidized substrate analogue 6-hydroxy-methyl-pterin monophosphate reveals how the HPPK and DHPS functional domains associate at both the ternary and quaternary levels
-
purified recombinant enzyme in complex with AMPCPP and different inhibitors, sitting-drop vapor diffusion method, mixing of 6.9 mg/ml protein in in 20 mM Tris-HCl buffer, pH 8.0, 100 mM NaCl, with reservoir solution containing 0.186 M sodium nitrate, 18.4% w/v PEG 3000, 2 mM MgCl2, 1 mM AMPCPP, and 1 mM inhibitor or 0.1 M Tris-HCl, pH 8.5, 0.2 M MgCl2, 20% PEG 8000, 0.05 M sodium thiocyanate, 1 mM AMPCPP, and 1 mM inhibitor, X-ray diffraction structure determination and analysis, molecular replacement
-
sitting drop vapor diffusion method, using 1.08 M sodium malonate pH 7, 0.09 M bis-Tris pH 6.5, 0.175 M sodium formate, and 0.01 M sodium acetate pH 4.6
-
X-ray diffraction crystal structure analysis of both the SaHPPK/inhibitor/cofactor analogue ternary and the SaHPPK/cofactor analogue binary complexes
-
hanging-drop method
-
purified recombinant HPPK in complex with 6-hydroxymethyl-7,8-dihydropterin and an ATP analogue AMPCPP, 8.0 mg/ml HPPK in 15 mM HP, 25 mM AMPCPP, 50 mM MgCl2 and 10 mM Tris-HCl, pH 8.0 s mixed with well solution containing 0.18 M ammonium acetate, 30% w/v PEG 4000, 20 mM imidazole, and 0.1 M sodium acetate, pH 4.6, 1-3 weeks, X-ray diffraction structure determination and analysis, molecular replacement
Q7CKD7