|
|
| (2 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| | + | |
| | ==STRUCTURAL BASIS FOR THE INHIBITION OF MAMMALIAN ADENYLYL CYCLASE BY MANT-GTP== | | ==STRUCTURAL BASIS FOR THE INHIBITION OF MAMMALIAN ADENYLYL CYCLASE BY MANT-GTP== |
| - | <StructureSection load='1u0h' size='340' side='right' caption='[[1u0h]], [[Resolution|resolution]] 2.90Å' scene=''> | + | <StructureSection load='1u0h' size='340' side='right'caption='[[1u0h]], [[Resolution|resolution]] 2.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1u0h]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Bovin Bovin], [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat] and [http://en.wikipedia.org/wiki/Canfa Canfa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1U0H OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1U0H FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1u0h]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus], [https://en.wikipedia.org/wiki/Canis_lupus_familiaris Canis lupus familiaris] and [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1U0H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1U0H FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FOK:FORSKOLIN'>FOK</scene>, <scene name='pdbligand=GSP:5-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE'>GSP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ONM:3-O-(N-METHYLANTHRANILOYL)-GUANOSINE-5-TRIPHOSPHATE'>ONM</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]] 2.9Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1tl7|1tl7]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FOK:FORSKOLIN'>FOK</scene>, <scene name='pdbligand=GSP:5-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE'>GSP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ONM:3-O-(N-METHYLANTHRANILOYL)-GUANOSINE-5-TRIPHOSPHATE'>ONM</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADCY5; ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9615 CANFA]), Adcy2; ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat]), GNAS; ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9913 BOVIN])</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=1u0h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1u0h OCA], [https://pdbe.org/1u0h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1u0h RCSB], [https://www.ebi.ac.uk/pdbsum/1u0h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1u0h 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=1u0h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1u0h OCA], [http://pdbe.org/1u0h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1u0h RCSB], [http://www.ebi.ac.uk/pdbsum/1u0h PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ADCY5_CANFA ADCY5_CANFA]] This is a membrane-bound, calcium-inhibitable adenylyl cyclase. [[http://www.uniprot.org/uniprot/GNAS2_BOVIN GNAS2_BOVIN]] Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(s) protein is involved in hormonal regulation of adenylate cyclase: it activates the cyclase in response to beta-adrenergic stimuli. [[http://www.uniprot.org/uniprot/ADCY2_RAT ADCY2_RAT]] This is a membrane-bound, calmodulin-insensitive adenylyl cyclase. | + | [https://www.uniprot.org/uniprot/ADCY5_CANLF ADCY5_CANLF] Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling (PubMed:1618857, PubMed:8428899, PubMed:10427002, PubMed:11087399, PubMed:15591060, PubMed:16766715, PubMed:19243146). Mediates signaling downstream of ADRB1. Regulates the increase of free cytosolic Ca(2+) in response to increased blood glucose levels and contributes to the regulation of Ca(2+)-dependent insulin secretion (By similarity).[UniProtKB:O95622]<ref>PMID:10427002</ref> <ref>PMID:11087399</ref> <ref>PMID:15591060</ref> <ref>PMID:1618857</ref> <ref>PMID:16766715</ref> <ref>PMID:19243146</ref> <ref>PMID:8428899</ref> Lacks catalytic activity by itself, but can associate with isoform 1 to form active adenylyl cyclase.<ref>PMID:8428899</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/u0/1u0h_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/u0/1u0h_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
| - | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1u0h ConSurf]. |
| | <div style="clear:both"></div> | | <div style="clear:both"></div> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| Line 32: |
Line 31: |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Adenylyl cyclase|Adenylyl cyclase]] | + | *[[3D Adenylyl cyclase 3D structures|3D Adenylyl cyclase 3D structures]] |
| - | *[[Guanine nucleotide-binding protein|Guanine nucleotide-binding protein]]
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Adenylate cyclase]] | + | [[Category: Bos taurus]] |
| - | [[Category: Bovin]] | + | [[Category: Canis lupus familiaris]] |
| - | [[Category: Buffalo rat]] | + | [[Category: Large Structures]] |
| - | [[Category: Canfa]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Gille, A]] | + | [[Category: Gille A]] |
| - | [[Category: Mou, T C]] | + | [[Category: Mou TC]] |
| - | [[Category: Seifert, R J]] | + | [[Category: Seifert RJ]] |
| - | [[Category: Sprang, S R]] | + | [[Category: Sprang SR]] |
| - | [[Category: Adenylyl cyclase]]
| + | |
| - | [[Category: Gsa]]
| + | |
| - | [[Category: Lyase]]
| + | |
| - | [[Category: Mant-gtp]]
| + | |
| Structural highlights
1u0h is a 3 chain structure with sequence from Bos taurus, Canis lupus familiaris and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.9Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
ADCY5_CANLF Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling (PubMed:1618857, PubMed:8428899, PubMed:10427002, PubMed:11087399, PubMed:15591060, PubMed:16766715, PubMed:19243146). Mediates signaling downstream of ADRB1. Regulates the increase of free cytosolic Ca(2+) in response to increased blood glucose levels and contributes to the regulation of Ca(2+)-dependent insulin secretion (By similarity).[UniProtKB:O95622][1] [2] [3] [4] [5] [6] [7] Lacks catalytic activity by itself, but can associate with isoform 1 to form active adenylyl cyclase.[8]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Membrane-bound mammalian adenylyl cyclase (mAC) catalyzes the synthesis of intracellular cyclic AMP from ATP and is activated by stimulatory G protein alpha subunits (Galpha(s)) and by forskolin (FSK). mACs are inhibited with high potency by 2 '(3')-O-(N-methylanthraniloyl) (MANT)-substituted nucleotides. In this study, the crystal structures of the complex between Galpha(s).GTPgammaS and the catalytic C1 and C2 domains from type V and type II mAC (VC1.IIC2), bound to FSK and either MANT-GTP.Mg(2+) or MANT-GTP.Mn(2+) have been determined. MANT-GTP coordinates two metal ions and occupies the same position in the catalytic site as P-site inhibitors and substrate analogs. However, the orientation of the guanine ring is reversed relative to that of the adenine ring. The MANT fluorophore resides in a hydrophobic pocket at the interface between the VC1 and IIC2 domains and prevents mAC from undergoing the "open" to "closed" domain rearrangement. The K(i) of MANT-GTP for inhibition of VC1.IIC2 is lower in the presence of mAC activators and lower in the presence of Mn(2+) compared with Mg(2+), indicating that the inhibitor binds more tightly to the catalytically most active form of the enzyme. Fluorescence resonance energy transfer-stimulated emission from the MANT fluorophore upon excitation of Trp-1020 in the MANT-binding pocket of IIC2 is also stronger in the presence of FSK. Mutational analysis of two non-conserved amino acids in the MANT-binding pocket suggests that residues outside of the binding site influence isoform selectivity toward MANT-GTP.
Structural basis for the inhibition of mammalian membrane adenylyl cyclase by 2 '(3')-O-(N-Methylanthraniloyl)-guanosine 5 '-triphosphate.,Mou TC, Gille A, Fancy DA, Seifert R, Sprang SR J Biol Chem. 2005 Feb 25;280(8):7253-61. Epub 2004 Dec 9. PMID:15591060[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Tesmer JJ, Sunahara RK, Johnson RA, Gosselin G, Gilman AG, Sprang SR. Two-metal-Ion catalysis in adenylyl cyclase. Science. 1999 Jul 30;285(5428):756-60. PMID:10427002
- ↑ Tesmer JJ, Dessauer CW, Sunahara RK, Murray LD, Johnson RA, Gilman AG, Sprang SR. Molecular basis for P-site inhibition of adenylyl cyclase. Biochemistry. 2000 Nov 28;39(47):14464-71. PMID:11087399
- ↑ Mou TC, Gille A, Fancy DA, Seifert R, Sprang SR. Structural basis for the inhibition of mammalian membrane adenylyl cyclase by 2 '(3')-O-(N-Methylanthraniloyl)-guanosine 5 '-triphosphate. J Biol Chem. 2005 Feb 25;280(8):7253-61. Epub 2004 Dec 9. PMID:15591060 doi:http://dx.doi.org/10.1074/jbc.M409076200
- ↑ Ishikawa Y, Katsushika S, Chen L, Halnon NJ, Kawabe J, Homcy CJ. Isolation and characterization of a novel cardiac adenylylcyclase cDNA. J Biol Chem. 1992 Jul 5;267(19):13553-7. PMID:1618857
- ↑ Mou TC, Gille A, Suryanarayana S, Richter M, Seifert R, Sprang SR. Broad specificity of mammalian adenylyl cyclase for interaction with 2',3'-substituted purine- and pyrimidine nucleotide inhibitors. Mol Pharmacol. 2006 Sep;70(3):878-86. Epub 2006 Jun 9. PMID:16766715 doi:http://dx.doi.org/10.1124/mol.106.026427
- ↑ Mou TC, Masada N, Cooper DM, Sprang SR. Structural basis for inhibition of mammalian adenylyl cyclase by calcium. Biochemistry. 2009 Apr 21;48(15):3387-97. PMID:19243146 doi:http://dx.doi.org/10.1021/bi802122k
- ↑ Katsushika S, Kawabe J, Homcy CJ, Ishikawa Y. In vivo generation of an adenylylcyclase isoform with a half-molecule motif. J Biol Chem. 1993 Feb 5;268(4):2273-6. PMID:8428899
- ↑ Katsushika S, Kawabe J, Homcy CJ, Ishikawa Y. In vivo generation of an adenylylcyclase isoform with a half-molecule motif. J Biol Chem. 1993 Feb 5;268(4):2273-6. PMID:8428899
- ↑ Mou TC, Gille A, Fancy DA, Seifert R, Sprang SR. Structural basis for the inhibition of mammalian membrane adenylyl cyclase by 2 '(3')-O-(N-Methylanthraniloyl)-guanosine 5 '-triphosphate. J Biol Chem. 2005 Feb 25;280(8):7253-61. Epub 2004 Dec 9. PMID:15591060 doi:http://dx.doi.org/10.1074/jbc.M409076200
|
