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| | <StructureSection load='5a7i' size='340' side='right'caption='[[5a7i]], [[Resolution|resolution]] 2.89Å' scene=''> | | <StructureSection load='5a7i' size='340' side='right'caption='[[5a7i]], [[Resolution|resolution]] 2.89Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5a7i]] is a 1 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=5A7I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5A7I FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5a7i]] is a 1 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=5A7I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5A7I FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B6K:BIPHENYL+3,3,4,4,5,5-HEXAKISPHOSPHATE'>B6K</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 2.89Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5a7j|5a7j]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B6K:BIPHENYL+3,3,4,4,5,5-HEXAKISPHOSPHATE'>B6K</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphoinositide_5-phosphatase Phosphoinositide 5-phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.36 3.1.3.36] </span></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=5a7i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5a7i OCA], [https://pdbe.org/5a7i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5a7i RCSB], [https://www.ebi.ac.uk/pdbsum/5a7i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5a7i 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=5a7i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5a7i OCA], [http://pdbe.org/5a7i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5a7i RCSB], [http://www.ebi.ac.uk/pdbsum/5a7i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5a7i ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/I5P2_HUMAN I5P2_HUMAN]] Hydrolyzes phosphatidylinositol 4,5-bisphosphate (PtIns(4,5)P2) and the signaling molecule phosphatidylinositol 1,4,5-trisphosphate (PtIns(1,4,5)P3), and thereby modulates cellular signaling events.<ref>PMID:7721860</ref> | + | [https://www.uniprot.org/uniprot/I5P2_HUMAN I5P2_HUMAN] Hydrolyzes phosphatidylinositol 4,5-bisphosphate (PtIns(4,5)P2) and the signaling molecule phosphatidylinositol 1,4,5-trisphosphate (PtIns(1,4,5)P3), and thereby modulates cellular signaling events.<ref>PMID:7721860</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| | *[[Phosphoinositide phosphatase|Phosphoinositide phosphatase]] | | *[[Phosphoinositide phosphatase|Phosphoinositide phosphatase]] |
| | + | *[[3D structures of inositol polyphosphate 5-phosphatase OCRL|3D structures of inositol polyphosphate 5-phosphatase OCRL]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Phosphoinositide 5-phosphatase]]
| + | [[Category: Cozier G]] |
| - | [[Category: Cozier, G]] | + | [[Category: Mills SJ]] |
| - | [[Category: Mills, S J]] | + | [[Category: Norldund P]] |
| - | [[Category: Norldund, P]] | + | [[Category: Potter BVL]] |
| - | [[Category: Potter, B V.L]] | + | [[Category: Silvander C]] |
| - | [[Category: Silvander, C]] | + | [[Category: Tresaugues L]] |
| - | [[Category: Tresaugues, L]] | + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Magnesium binding]]
| + | |
| - | [[Category: Phosphoinositides signalling]]
| + | |
| - | [[Category: Protein-inhbitor complex]]
| + | |
| - | [[Category: Sgc]]
| + | |
| - | [[Category: Signalling]]
| + | |
| - | [[Category: Structural genomic]]
| + | |
| Structural highlights
5a7i is a 1 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 2.89Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
I5P2_HUMAN Hydrolyzes phosphatidylinositol 4,5-bisphosphate (PtIns(4,5)P2) and the signaling molecule phosphatidylinositol 1,4,5-trisphosphate (PtIns(1,4,5)P3), and thereby modulates cellular signaling events.[1]
Publication Abstract from PubMed
The inositol polyphosphate 5-phosphatase INPP5B hydrolyzes the 5-phosphate group from water- and lipid-soluble signaling messengers. Two synthetic benzene and biphenyl polyphosphates (BzP/BiPhPs), simplified surrogates of inositol phosphates and phospholipid headgroups, were identified by thermodynamic studies as potent INPP5B ligands. The X-ray structure of the complex between INPP5B and biphenyl 3,3',4,4',5,5'-hexakisphosphate [BiPh(3,3',4,4',5,5')P6, IC50 5.5 muM] was determined at 2.89 A resolution. One inhibitor pole locates in the phospholipid headgroup binding site and the second solvent-exposed ring binds to the His-Tag of another INPP5B molecule, while a molecule of inorganic phosphate is also present in the active site. Benzene 1,2,3-trisphosphate [Bz(1,2,3)P3] [one ring of BiPh(3,3',4,4',5,5')P6] inhibits INPP5B ca. 6-fold less potently. Co-crystallization with benzene 1,2,4,5-tetrakisphosphate [Bz(1,2,4,5)P4, IC50 = 6.3 muM] yielded a structure refined at 2.9 A resolution. Conserved residues among the 5-phosphatase family mediate interactions with Bz(1,2,4,5)P4 and BiPh(3,3',4,4',5,5')P6 similar to those with the polar groups present in positions 1, 4, 5, and 6 on the inositol ring of the substrate. 5-Phosphatase specificity most likely resides in the variable zone located close to the 2- and 3-positions of the inositol ring, offering insights to inhibitor design. We propose that the inorganic phosphate present in the INPP5B-BiPh(3,3',4,4',5,5')P6 complex mimics the postcleavage substrate 5-phosphate released by INPP5B in the catalytic site, allowing elucidation of two new key features in the catalytic mechanism proposed for the family of phosphoinositide 5-phosphatases: first, the involvement of the conserved Arg-451 in the interaction with the 5-phosphate and second, identification of the water molecule that initiates 5-phosphate hydrolysis. Our model also has implications for the proposed "moving metal" mechanism.
Crystal Structures of Type-II Inositol Polyphosphate 5-Phosphatase INPP5B with Synthetic Inositol Polyphosphate Surrogates Reveal New Mechanistic Insights for the Inositol 5-Phosphatase Family.,Mills SJ, Silvander C, Cozier G, Tresaugues L, Nordlund P, Potter BV Biochemistry. 2016 Mar 8;55(9):1384-97. doi: 10.1021/acs.biochem.5b00838. Epub, 2016 Feb 29. PMID:26854536[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Jefferson AB, Majerus PW. Properties of type II inositol polyphosphate 5-phosphatase. J Biol Chem. 1995 Apr 21;270(16):9370-7. PMID:7721860
- ↑ Mills SJ, Silvander C, Cozier G, Tresaugues L, Nordlund P, Potter BV. Crystal Structures of Type-II Inositol Polyphosphate 5-Phosphatase INPP5B with Synthetic Inositol Polyphosphate Surrogates Reveal New Mechanistic Insights for the Inositol 5-Phosphatase Family. Biochemistry. 2016 Mar 8;55(9):1384-97. doi: 10.1021/acs.biochem.5b00838. Epub, 2016 Feb 29. PMID:26854536 doi:http://dx.doi.org/10.1021/acs.biochem.5b00838
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