5kmb

Human Histidine Triad Nucleotide Binding Protein 1 (hHint1) H112N mutant nucleoside L-Trp phosphoramidate substrate complex

spinqualitylabelsall models 5kmb, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5kmb is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.6Å Ligands: 6UT, CL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function HINT1_HUMAN Hydrolyzes adenosine 5'-monophosphoramidate substrates such as AMP-morpholidate, AMP-N-alanine methyl ester, AMP-alpha-acetyl lysine methyl ester and AMP-NH2 (By similarity). Publication Abstract from PubMed Nucleotide analogs that incorporate a metabolically labile nucleoside phosphoramidate (a ProTide) have found utility as prodrugs. In humans, ProTides can be cleaved by human histidine triad nucleotide binding protein 1 (hHint1) to expose the nucleotide monophosphate. Activation by this route circumvents highly selective nucleoside kinases that limit the use of nucleosides as prodrugs. To better understand the diversity of potential substrates of hHint1, we created and studied a series of phosphoramidate nucleosides. Using a combination of enzyme kinetics, X-ray crystallography, and isothermal titration calorimetry with both wild-type and inactive mutant enzymes, we have been able to explore the energetics of substrate binding and establish a structural basis for catalytic efficiency. Diverse nucleobases are well tolerated, but portions of the ribose are needed to position substrates for catalysis. Beneficial characteristics of the amine leaving group are also revealed. Structural principles revealed by these results may be exploited to tune the rate of substrate hydrolysis to strategically alter the intracellular release of the product nucleoside monophosphate from the ProTide. A Crystal Structure-Based Guide to the Design of Human Histidine Triad Nucleotide Binding Protein 1 (hHint1) Activated ProTides.,Maize KM, Shah R, Strom A, Kumarapperuma SC, Zhou AL, Wagner CR, Finzel BC Mol Pharm. 2017 Oct 2. doi: 10.1021/acs.molpharmaceut.7b00664. PMID:28968488 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Histidine triad nucleotide-binding protein 3D structures

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