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| | ==Crystal structure of human soluble Adenylyl Cyclase with the inhibitor bithionol== | | ==Crystal structure of human soluble Adenylyl Cyclase with the inhibitor bithionol== |
| - | <StructureSection load='5d0r' size='340' side='right' caption='[[5d0r]], [[Resolution|resolution]] 2.24Å' scene=''> | + | <StructureSection load='5d0r' size='340' side='right'caption='[[5d0r]], [[Resolution|resolution]] 2.24Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5d0r]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5D0R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5D0R FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5d0r]] 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=5D0R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5D0R FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=B1T:2,2-SULFANEDIYLBIS(4,6-DICHLOROPHENOL)'>B1T</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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]] 2.24Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=B1T:2,2-SULFANEDIYLBIS(4,6-DICHLOROPHENOL)'>B1T</scene>, <scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4clf|4clf]], [[4clk|4clk]], [[4cll|4cll]], [[4clp|4clp]], [[4cls|4cls]], [[4clt|4clt]], [[4clu|4clu]], [[4clw|4clw]], [[4cly|4cly]], [[4clz|4clz]], [[4cm2|4cm2]]</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=5d0r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5d0r OCA], [https://pdbe.org/5d0r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5d0r RCSB], [https://www.ebi.ac.uk/pdbsum/5d0r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5d0r ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Adenylate_cyclase Adenylate cyclase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.6.1.1 4.6.1.1] </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=5d0r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5d0r OCA], [http://pdbe.org/5d0r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5d0r RCSB], [http://www.ebi.ac.uk/pdbsum/5d0r PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/ADCYA_HUMAN ADCYA_HUMAN]] Idiopathic hypercalciuria. Disease susceptibility is associated with variations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/ADCYA_HUMAN ADCYA_HUMAN] Idiopathic hypercalciuria. Disease susceptibility is associated with variations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ADCYA_HUMAN ADCYA_HUMAN]] Soluble adenylyl cyclase that has a critical role in mammalian spermatogenesis. Produces the cAMP which mediates in part the cAMP-responsive nuclear factors indispensable for maturation of sperm in the epididymis. Induces capacitation, the maturational process that sperm undergo prior to fertilization. May be the bicarbonate sensor. Involved in ciliary beat regulation.<ref>PMID:15659711</ref> <ref>PMID:17591988</ref> | + | [https://www.uniprot.org/uniprot/ADCYA_HUMAN ADCYA_HUMAN] Soluble adenylyl cyclase that has a critical role in mammalian spermatogenesis. Produces the cAMP which mediates in part the cAMP-responsive nuclear factors indispensable for maturation of sperm in the epididymis. Induces capacitation, the maturational process that sperm undergo prior to fertilization. May be the bicarbonate sensor. Involved in ciliary beat regulation.<ref>PMID:15659711</ref> <ref>PMID:17591988</ref> |
| | <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 5d0r" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5d0r" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[3D Adenylyl cyclase 3D structures|3D Adenylyl cyclase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Adenylate cyclase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Kleinboelting, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Steegborn, C]] | + | [[Category: Kleinboelting S]] |
| - | [[Category: Lyase]] | + | [[Category: Steegborn C]] |
| Structural highlights
5d0r 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 2.24Å |
| Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
ADCYA_HUMAN Idiopathic hypercalciuria. Disease susceptibility is associated with variations affecting the gene represented in this entry.
Function
ADCYA_HUMAN Soluble adenylyl cyclase that has a critical role in mammalian spermatogenesis. Produces the cAMP which mediates in part the cAMP-responsive nuclear factors indispensable for maturation of sperm in the epididymis. Induces capacitation, the maturational process that sperm undergo prior to fertilization. May be the bicarbonate sensor. Involved in ciliary beat regulation.[1] [2]
Publication Abstract from PubMed
The signaling molecule cAMP regulates functions ranging from bacterial transcription to mammalian memory. In mammals, cAMP is synthesized by nine transmembrane adenylyl cyclases (ACs) and one soluble AC (sAC). Despite similarities in their catalytic domains, these ACs differ in regulation. Transmembrane ACs respond to G proteins, whereas sAC is uniquely activated by bicarbonate. Via bicarbonate regulation, sAC acts as a physiological sensor for pH/bicarbonate/CO2, and it has been implicated as a therapeutic target, e.g. for diabetes, glaucoma, and a male contraceptive. Here we identify the bisphenols bithionol and hexachlorophene as potent, sAC-specific inhibitors. Inhibition appears mostly non-competitive with the substrate ATP, indicating that they act via an allosteric site. To analyze the interaction details, we solved a crystal structure of an sAC.bithionol complex. The structure reveals that the compounds are selective for sAC because they bind to the sAC-specific, allosteric binding site for the physiological activator bicarbonate. Structural comparison of the bithionol complex with apo-sAC and other sAC.ligand complexes along with mutagenesis experiments reveals an allosteric mechanism of inhibition; the compound induces rearrangements of substrate binding residues and of Arg(176), a trigger between the active site and allosteric site. Our results thus provide 1) novel insights into the communication between allosteric regulatory and active sites, 2) a novel mechanism for sAC inhibition, and 3) pharmacological compounds targeting this allosteric site and utilizing this mode of inhibition. These studies provide support for the future development of sAC-modulating drugs.
Bithionol Potently Inhibits Human Soluble Adenylyl Cyclase through Binding to the Allosteric Activator Site.,Kleinboelting S, Ramos-Espiritu L, Buck H, Colis L, van den Heuvel J, Glickman JF, Levin LR, Buck J, Steegborn C J Biol Chem. 2016 Apr 29;291(18):9776-84. doi: 10.1074/jbc.M115.708255. Epub 2016, Mar 9. PMID:26961873[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Geng W, Wang Z, Zhang J, Reed BY, Pak CY, Moe OW. Cloning and characterization of the human soluble adenylyl cyclase. Am J Physiol Cell Physiol. 2005 Jun;288(6):C1305-16. Epub 2005 Jan 19. PMID:15659711 doi:http://dx.doi.org/10.1152/ajpcell.00584.2004
- ↑ Schmid A, Sutto Z, Nlend MC, Horvath G, Schmid N, Buck J, Levin LR, Conner GE, Fregien N, Salathe M. Soluble adenylyl cyclase is localized to cilia and contributes to ciliary beat frequency regulation via production of cAMP. J Gen Physiol. 2007 Jul;130(1):99-109. PMID:17591988 doi:http://dx.doi.org/jgp.200709784
- ↑ Kleinboelting S, Ramos-Espiritu L, Buck H, Colis L, van den Heuvel J, Glickman JF, Levin LR, Buck J, Steegborn C. Bithionol Potently Inhibits Human Soluble Adenylyl Cyclase through Binding to the Allosteric Activator Site. J Biol Chem. 2016 Apr 29;291(18):9776-84. doi: 10.1074/jbc.M115.708255. Epub 2016, Mar 9. PMID:26961873 doi:http://dx.doi.org/10.1074/jbc.M115.708255
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