User:Michael Lartey/Sandbox: Difference between revisions

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'''Introduction'''
{{STRUCTURE_1e2h |  PDB=1e2h |  SCENE=  }}
 
===Introduction===


Thymidine kinases (TKs) catalyze the first phosphorylation step of deoxyribonucleosides in the salvage pathway in DNA synthesis. These enzymes belong to deoxyribonucleotide kinases (dNKs)
Thymidine kinases (TKs) catalyze the first phosphorylation step of deoxyribonucleosides in the salvage pathway in DNA synthesis. These enzymes belong to deoxyribonucleotide kinases (dNKs)
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[[Image:DT phosphorylation.png|center]]
[[Image:DT phosphorylation.png|center]]


'''Structure and uses'''
===Structure and uses===
 
Herpes simplex virus thymidine kinase (TKHSV1) is a homodimeric α/β- protein comprising of five β-sheets and twelve α-helices per unit. Each unit also has a sulfate ion. It has a two-fold axis. At the interphase are three helices from each monomer where non-polar side chains interact.  [[Image:Chain connectivity in TK HSV1.png|thumb]] TKHSV1 is less specific than the human analog; it catalyzes the phosphorylation of pyrimidines, purines and a wide range of ribose analogs. The broad specificity of TKHSV1 has found a lot of therapeutic use in virally directed enzyme prodrug therapy in the treatment of herpes and cancer. The enzyme phosphorylates a non-toxic prodrug to a toxic form that inhibits viral replication. Drugs such as acyclovir for herpes treatment, AZT for HIV treatment and gancyclovir for cancer treatment work in this manner.  The drawback with these therapeutic procedures is the poor binding of the enzyme to the drug. A higher dosage is required and this leads to toxicity.


Herpes simplex virus thymidine kinase (TKHSV1) is a homodimeric α/β- protein comprising of five β-sheets and twelve α-helices per unit. Each unit also has a sulfate ion. It has a two-fold axis. At the interphase are three helices from each monomer where non-polar side chains interact. TKHSV1 is less specific than the human analog; it catalyzes the phosphorylation of pyrimidines, purines and a wide range of ribose analogs. The broad specificity of TKHSV1 has found a lot of therapeutic use in virally directed enzyme prodrug therapy in the treatment of herpes and cancer. The enzyme phosphorylates a non-toxic prodrug to a toxic form that inhibits viral replication. Drugs such as acyclovir for herpes treatment, AZT for HIV treatment and gancyclovir for cancer treatment work in this manner.  The drawback with these therapeutic procedures is the poor binding of the enzyme to the drug. A higher dosage is required and this leads to toxicity.  
[[Image:Conservation.png|thumb|left]]


===Catalysis and Ligand Binding===


'''Catalysis and Ligand Binding'''
At the active center of the enzyme is a glycine-rich P-loop that connects b1 and a1 to form a giant anion hole. The hole accommodates the β-phosphoryl group of ATP, one of its natural substrates. The other natural substrate, deoxythymidine (dT), is located in the pocket formed by a3, a4 and a5. Drugs also insert into this pocket for phosphorylation. ATP binds at the giant anion hole which has a positive charge. This active center is highly conserved  in TKs as shown by the consurf analysis.


At the active center of the enzyme is a glycine P-loop that connects b1 and a1 to form a giant anion hole. The hole accommodates the β-phosphoryl group of ATP, one of its natural substrates. The other natural substrate, deoxythymidine (dT), is located in the pocket formed by a3, a4 and a5. Drugs also insert into this pocket for phosphorylation. ATP binds at the giant anion hole. This active center is highly reserved  in TKs.


Replace the PDB id after the STRUCTURE_ and after PDB= to load
[[Image:Surface charge distribution.png|thumb]]
and display another structure.


{{STRUCTURE_1e2h |  PDB=1e2h |  SCENE= }}
 
 
===References===
 
Christine Wurth, Ulrich Kessler, Joachim Vogt, Georg E. Schulz, Gerd Folkers, Leonardo Scapozza. (2001) ''Protein Sci''. '''10''': 63-73
Graham Darby, Brendan A. Larder, Moira M. Inglis (1986) ''J. gen. Virol''. '''67:'''753-758
Joachim Vogt, Remo Perozzo, Alex Pautsch, Andrea Prota, Pierre Schelling, Bea Pilger, Gerg Folkers, Leonardo Scapozza, Georg E. Schulz(2000) ''PROTEINS: Structure, Function and Genetics'' '''41''': 545-553
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