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2gvd

From Proteopedia

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Complex Of Gs- With The Catalytic Domains Of Mammalian Adenylyl Cyclase: Complex With TNP-ATP and Mn

Structural highlights

2gvd 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 adenylyl cyclases (mACs) play an important role in signal transduction and are therefore potential drug targets. Earlier, we identified 2',3'-O-(N-methylanthraniloyl) (MANT)-substituted purine nucleotides as a novel class of highly potent competitive mAC inhibitors (Ki values in the 10 nM range). MANT nucleotides discriminate among various mAC isoforms through differential interactions with a binding pocket localized at the interface between the C1 and C2 domains of mAC. In this study, we examine the structure/activity relationships for 2',3'-substituted nucleotides and compare the crystal structures of mAC catalytic domains (VC1:IIC2) bound to MANT-GTP, MANT-ATP, and 2',3'-(2,4,6-trinitrophenyl) (TNP)-ATP. TNP-substituted purine and pyrimidine nucleotides inhibited VC1:IIC2 with moderately high potency (Ki values in the 100 nM range). Elongation of the linker between the ribosyl group and the MANT group and substitution of N-adenine atoms with MANT reduces inhibitory potency. Crystal structures show that MANT-GTP, MANT-ATP, and TNP-ATP reside in the same binding pocket in the VC1:IIC2 protein complex, but there are substantial differences in interactions of base, fluorophore, and polyphosphate chain of the inhibitors with mAC. Fluorescence emission and resonance transfer spectra also reflect differences in the interaction between MANT-ATP and VC1:IIC2 relative to MANT-GTP. Our data are indicative of a three-site mAC pharmacophore; the 2',3'-O-ribosyl substituent and the polyphosphate chain have the largest impact on inhibitor affinity and the nucleotide base has the least. The mAC binding site exhibits broad specificity, accommodating various bases and fluorescent groups at the 2',3'-O-ribosyl position. These data should greatly facilitate the rational design of potent, isoform-selective mAC inhibitors.

Broad specificity of mammalian adenylyl cyclase for interaction with 2',3'-substituted purine- and pyrimidine nucleotide inhibitors.,Mou TC, Gille A, Suryanarayana S, Richter M, Seifert R, Sprang SR Mol Pharmacol. 2006 Sep;70(3):878-86. Epub 2006 Jun 9. PMID:16766715^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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, 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

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2gvd"

@@ Line 1: / Line 1: @@
 ==Complex Of Gs- With The Catalytic Domains Of Mammalian Adenylyl Cyclase: Complex With TNP-ATP and Mn==
-<StructureSection load='2gvd' size='340' side='right' caption='[[2gvd]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
+<StructureSection load='2gvd' size='340' side='right'caption='[[2gvd]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2gvd]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus], [http://en.wikipedia.org/wiki/Canis_lupus_familiaris Canis lupus familiaris] and [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GVD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2GVD FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2gvd]] 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=2GVD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2GVD FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=128:SPIRO(2,4,6-TRINITROBENZENE[1,2A]-2O,3O-METHYLENE-ADENINE-TRIPHOSPHATE'>128</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FKP:METHYLPIPERAZINOFORSKOLIN'>FKP</scene>, <scene name='pdbligand=GSP:5-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE'>GSP</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene><br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9&#8491;</td></tr>
-<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1tl7|1tl7]], [[1u0h|1u0h]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=128:SPIRO(2,4,6-TRINITROBENZENE[1,2A]-2O,3O-METHYLENE-ADENINE-TRIPHOSPHATE'>128</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FKP:METHYLPIPERAZINOFORSKOLIN'>FKP</scene>, <scene name='pdbligand=GSP:5-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE'>GSP</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr>
-<tr><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 Canis lupus familiaris]), Adcy2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Rattus norvegicus]), GNAS, GNAS1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9913 Bos taurus])</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=2gvd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gvd OCA], [https://pdbe.org/2gvd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2gvd RCSB], [https://www.ebi.ac.uk/pdbsum/2gvd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2gvd ProSAT]</span></td></tr>
-<tr><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>
+</table>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2gvd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gvd OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2gvd RCSB], [http://www.ebi.ac.uk/pdbsum/2gvd PDBsum]</span></td></tr>
+== Function ==
-<table>
+[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 ==
 [[Image:Consurf_key_small.gif|200px|right]]
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gv/2gvd_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gv/2gvd_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
   </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=2gvd ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 27: / Line 28: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2gvd" style="background-color:#fffaf0;"></div>
 ==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/>
 __TOC__
 </StructureSection>
-[[Category: Adenylate cyclase]]
 [[Category: Bos taurus]]
 [[Category: Canis lupus familiaris]]
+[[Category: Large Structures]]
 [[Category: Rattus norvegicus]]
-[[Category: Mou, T C.]]
+[[Category: Mou T-C]]
-[[Category: Sprang, S R.]]
+[[Category: Sprang SR]]
-[[Category: Adenylyl cyclase]]
-[[Category: Gsa]]
-[[Category: Lyase]]
-[[Category: Tnp-atp]]

2gvd

From Proteopedia

Current revision

Complex Of Gs- With The Catalytic Domains Of Mammalian Adenylyl Cyclase: Complex With TNP-ATP and Mn

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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