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| | ==Human Histidine Triad Nucleotide Binding Protein 1 (hHint1) CMP catalytic product complex== | | ==Human Histidine Triad Nucleotide Binding Protein 1 (hHint1) CMP catalytic product complex== |
| - | <StructureSection load='5km2' size='340' side='right' caption='[[5km2]], [[Resolution|resolution]] 1.25Å' scene=''> | + | <StructureSection load='5km2' size='340' side='right'caption='[[5km2]], [[Resolution|resolution]] 1.25Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5km2]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KM2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KM2 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5km2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KM2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KM2 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C5P:CYTIDINE-5-MONOPHOSPHATE'>C5P</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.25Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3tw2|3tw2]], [[5ipb|5ipb]], [[5ipc|5ipc]], [[5ipd|5ipd]], [[5ipe|5ipe]], [[5kly|5kly]], [[5km0|5km0]], [[5klz|5klz]], [[5km1|5km1]], [[5km3|5km3]], [[5km4|5km4]], [[5km5|5km5]], [[5km6|5km6]], [[5km7|5km7]], [[5km8|5km8]], [[5km9|5km9]], [[5kma|5kma]], [[5kmb|5kmb]], [[5kmc|5kmc]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C5P:CYTIDINE-5-MONOPHOSPHATE'>C5P</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HINT1, HINT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5km2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5km2 OCA], [https://pdbe.org/5km2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5km2 RCSB], [https://www.ebi.ac.uk/pdbsum/5km2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5km2 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5km2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5km2 OCA], [http://pdbe.org/5km2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5km2 RCSB], [http://www.ebi.ac.uk/pdbsum/5km2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5km2 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/HINT1_HUMAN 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). | + | [https://www.uniprot.org/uniprot/HINT1_HUMAN 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). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5km2" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5km2" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Histidine triad nucleotide-binding protein 3D structures|Histidine triad nucleotide-binding protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Finzel, B C]] | + | [[Category: Large Structures]] |
| - | [[Category: Maize, K M]] | + | [[Category: Finzel BC]] |
| - | [[Category: Hint]] | + | [[Category: Maize KM]] |
| - | [[Category: Histidine triad]]
| + | |
| - | [[Category: Hit]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| Structural highlights
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Maize KM, Shah R, Strom A, Kumarapperuma SC, Zhou AL, Wagner CR, Finzel BC. A Crystal Structure-Based Guide to the Design of Human Histidine Triad Nucleotide Binding Protein 1 (hHint1) Activated ProTides. Mol Pharm. 2017 Oct 2. doi: 10.1021/acs.molpharmaceut.7b00664. PMID:28968488 doi:http://dx.doi.org/10.1021/acs.molpharmaceut.7b00664
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