Human Histidine Triad Nucleotide Binding Protein 1 Essay

Human Histidine Triad Nucleotide Binding Protein 1 Essay

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Human Histidine Triad Nucleotide Binding protein 1 (hHint1) has emerged a protein of interest due to its widespread expression, and mouse knockouts exhibiting multiple central nervous system (CNS) phenotypes. hHint1 is a member of a superfamily Histidine Triad (HIT) proteins characterize by their conserved nucleotide binding motif, His-X-His-X-His-XX, where X is a hydrophobic residue. hHint1 is a homodimer and possesses nucleoside phosphoramidase and acyl-AMP hydrolase activity, with preference for purine over pyrimidine nucleosides. Using NMR studies Shapiro and coworkers determined the dissociation constant of purine nucleoside monophosphate for Hint1 to be 67 ± 0.5 μM. Structural and kinetic studies have indicated that hHint1 possess two identical and independent nucleotide-binding subunits. Each monomer consists of five anti-parallel β sheets and an alpha helix motif. A conserved string of hydrophobic residues in or adjacent to the β sheets creates a binding pocket (S1) for the purine base, while polar residues for the binding of the ribose sugar. The monophosphate group interacts with polar and partially positive histidine residues. The side chains in the nucleoside phosphoramidates or acyl-AMP can occupy relative shallow and solvent accessible pocket containing the only tryptophan residues in hHint1. A nucleophilic histidine residue forming the part of the triad and active site of hHint1 is responsible for the catalysis. Detailed investigation on the kinetic mechanism of hHint1 have established that the mechanism proceeds via fast formation of the nucleotidylated-His intermediate, followed by the rate limiting step of water mediated hydrolysis and release of the nucleoside monophosphate from the active site. The phosphoram...

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... 0.1 μM with an n value of 1.00 ± 0.1 indicating one binding site per hHint1 monomer. Bio-AMS binds approximately 11 and 209 fold more tightly than TrpGc and GMP. The thermodynamic parameters are listed in Table.1. The binding of Bio-AMS is solely enthalpically driven with an unfavorable entropic component. The increased enthalpic contribution indicates that interaction between protein and ligand is primarily driven by hydrogen bonding and electrostatic interactions, while unfavorable entropy indicates minimal contribution from the potential hydrophobic interaction of the biotin side chain with the protein. In addition the thermodynamic parameters indicated that the binding affinity differences observed with Bio-AMS and TrpGc can be primarily attributed to the increased enthalpic contribution resulting in the overall increase in the favorable free energy of binding.

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