1u0h

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(New page: 200px<br /><applet load="1u0h" size="450" color="white" frame="true" align="right" spinBox="true" caption="1u0h, resolution 2.90&Aring;" /> '''STRUCTURAL BASIS FOR...)
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[[Image:1u0h.gif|left|200px]]<br /><applet load="1u0h" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1u0h, resolution 2.90&Aring;" />
 
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'''STRUCTURAL BASIS FOR THE INHIBITION OF MAMMALIAN ADENYLYL CYCLASE BY MANT-GTP'''<br />
 
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==Overview==
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==STRUCTURAL BASIS FOR THE INHIBITION OF MAMMALIAN ADENYLYL CYCLASE BY MANT-GTP==
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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.
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<StructureSection load='1u0h' size='340' side='right'caption='[[1u0h]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
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== Structural highlights ==
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<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>
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</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>
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<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>
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<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>
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</table>
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== Function ==
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[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/u0/1u0h_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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==About this Structure==
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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<ref>PMID:15591060</ref>
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1U0H is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences 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] with MG, CL, GSP, FOK and ONM as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1U0H OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15591060 15591060]
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</div>
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[[Category: Adenylate cyclase]]
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<div class="pdbe-citations 1u0h" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[3D Adenylyl cyclase 3D structures|3D Adenylyl cyclase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Bos taurus]]
[[Category: Bos taurus]]
[[Category: Canis lupus familiaris]]
[[Category: Canis lupus familiaris]]
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[[Category: Protein complex]]
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[[Category: Large Structures]]
[[Category: Rattus norvegicus]]
[[Category: Rattus norvegicus]]
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[[Category: Gille, A.]]
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[[Category: Gille A]]
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[[Category: Mou, T.C.]]
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[[Category: Mou TC]]
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[[Category: Seifert, R.J.]]
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[[Category: Seifert RJ]]
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[[Category: Sprang, S.R.]]
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[[Category: Sprang SR]]
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[[Category: CL]]
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[[Category: FOK]]
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[[Category: GSP]]
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[[Category: MG]]
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[[Category: ONM]]
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[[Category: adenylyl cyclase]]
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[[Category: gsa]]
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[[Category: mant-gtp]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 03:44:55 2007''
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Current revision

STRUCTURAL BASIS FOR THE INHIBITION OF MAMMALIAN ADENYLYL CYCLASE BY MANT-GTP

PDB ID 1u0h

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