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3ah8

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Structure of heterotrimeric G protein Galpha-q beta gamma in complex with an inhibitor YM-254890

Structural highlights

3ah8 is a 4 chain structure with sequence from Bos taurus, Chromobacterium sp., Mus musculus 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

GNAQ_MOUSE Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. Regulates B-cell selection and survival and is required to prevent B-cell-dependent autoimmunity. Regulates chemotaxis of BM-derived neutrophils and dendritic cells (in vitro).^[1] ^[2] GNAI1_RAT Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.^[3]

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

Heterotrimeric GTP-binding proteins (G proteins) transmit extracellular stimuli perceived by G protein-coupled receptors (GPCRs) to intracellular signaling cascades. Hundreds of GPCRs exist in humans and are the targets of a large percentage of the pharmaceutical drugs used today. Because G proteins are regulated by GPCRs, small molecules that directly modulate G proteins have the potential to become therapeutic agents. However, strategies to develop modulators have been hampered by a lack of structural knowledge of targeting sites for specific modulator binding. Here we present the mechanism of action of the cyclic depsipeptide YM-254890, which is a recently discovered G(q)-selective inhibitor. YM-254890 specifically inhibits the GDP/GTP exchange reaction of alpha subunit of G(q) protein (Galpha(q)) by inhibiting the GDP release from Galpha(q). X-ray crystal structure analysis of the Galpha(q)betagamma-YM-254890 complex shows that YM-254890 binds the hydrophobic cleft between two interdomain linkers connecting the GTPase and helical domains of the Galpha(q). The binding stabilizes an inactive GDP-bound form through direct interactions with switch I and impairs the linker flexibility. Our studies provide a novel targeting site for the development of small molecules that selectively inhibit each Galpha subunit and an insight into the molecular mechanism of G protein activation.

Structural basis for the specific inhibition of heterotrimeric Gq protein by a small molecule.,Nishimura A, Kitano K, Takasaki J, Taniguchi M, Mizuno N, Tago K, Hakoshima T, Itoh H Proc Natl Acad Sci U S A. 2010 Jul 16. PMID:20639466^[4]

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

References

↑ Shi G, Partida-Sanchez S, Misra RS, Tighe M, Borchers MT, Lee JJ, Simon MI, Lund FE. Identification of an alternative G{alpha}q-dependent chemokine receptor signal transduction pathway in dendritic cells and granulocytes. J Exp Med. 2007 Oct 29;204(11):2705-18. Epub 2007 Oct 15. PMID:17938235 doi:10.1084/jem.20071267
↑ Misra RS, Shi G, Moreno-Garcia ME, Thankappan A, Tighe M, Mousseau B, Kusser K, Becker-Herman S, Hudkins KL, Dunn R, Kehry MR, Migone TS, Marshak-Rothstein A, Simon M, Randall TD, Alpers CE, Liggitt D, Rawlings DJ, Lund FE. G alpha q-containing G proteins regulate B cell selection and survival and are required to prevent B cell-dependent autoimmunity. J Exp Med. 2010 Aug 2;207(8):1775-89. doi: 10.1084/jem.20092735. Epub 2010 Jul, 12. PMID:20624888 doi:10.1084/jem.20092735
↑ Shu FJ, Ramineni S, Amyot W, Hepler JR. Selective interactions between Gi alpha1 and Gi alpha3 and the GoLoco/GPR domain of RGS14 influence its dynamic subcellular localization. Cell Signal. 2007 Jan;19(1):163-76. Epub 2006 Jul 25. PMID:16870394 doi:http://dx.doi.org/10.1016/j.cellsig.2006.06.002
↑ Nishimura A, Kitano K, Takasaki J, Taniguchi M, Mizuno N, Tago K, Hakoshima T, Itoh H. Structural basis for the specific inhibition of heterotrimeric Gq protein by a small molecule. Proc Natl Acad Sci U S A. 2010 Jul 16. PMID:20639466

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/3ah8"

@@ Line 1: / Line 1: @@
-[[Image:3ah8.png|left|200px]]
-{{STRUCTURE_3ah8|  PDB=3ah8  |  SCENE=  }}
+==Structure of heterotrimeric G protein Galpha-q beta gamma in complex with an inhibitor YM-254890==
+<StructureSection load='3ah8' size='340' side='right'caption='[[3ah8]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[3ah8]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus], [https://en.wikipedia.org/wiki/Chromobacterium_sp. Chromobacterium sp.], [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus] 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=3AH8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3AH8 FirstGlance]. <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 id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=DAM:N-METHYL-ALPHA-BETA-DEHYDROALANINE'>DAM</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=HF2:(2R)-2-HYDROXY-3-PHENYLPROPANOIC+ACID'>HF2</scene>, <scene name='pdbligand=HL2:(2S,3R)-2-AMINO-3-HYDROXY-4-METHYLPENTANOIC+ACID'>HL2</scene>, <scene name='pdbligand=MAA:N-METHYL-L-ALANINE'>MAA</scene>, <scene name='pdbligand=OTH:N,O-DIMETHYL-L-THREONINE'>OTH</scene>, <scene name='pdbligand=THC:N-METHYLCARBONYLTHREONINE'>THC</scene></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=3ah8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ah8 OCA], [https://pdbe.org/3ah8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ah8 RCSB], [https://www.ebi.ac.uk/pdbsum/3ah8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ah8 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/GNAQ_MOUSE GNAQ_MOUSE] Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. Regulates B-cell selection and survival and is required to prevent B-cell-dependent autoimmunity. Regulates chemotaxis of BM-derived neutrophils and dendritic cells (in vitro).<ref>PMID:17938235</ref> <ref>PMID:20624888</ref> [https://www.uniprot.org/uniprot/GNAI1_RAT GNAI1_RAT] Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.<ref>PMID:16870394</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/ah/3ah8_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/main_output.php?pdb_ID=3ah8 ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Heterotrimeric GTP-binding proteins (G proteins) transmit extracellular stimuli perceived by G protein-coupled receptors (GPCRs) to intracellular signaling cascades. Hundreds of GPCRs exist in humans and are the targets of a large percentage of the pharmaceutical drugs used today. Because G proteins are regulated by GPCRs, small molecules that directly modulate G proteins have the potential to become therapeutic agents. However, strategies to develop modulators have been hampered by a lack of structural knowledge of targeting sites for specific modulator binding. Here we present the mechanism of action of the cyclic depsipeptide YM-254890, which is a recently discovered G(q)-selective inhibitor. YM-254890 specifically inhibits the GDP/GTP exchange reaction of alpha subunit of G(q) protein (Galpha(q)) by inhibiting the GDP release from Galpha(q). X-ray crystal structure analysis of the Galpha(q)betagamma-YM-254890 complex shows that YM-254890 binds the hydrophobic cleft between two interdomain linkers connecting the GTPase and helical domains of the Galpha(q). The binding stabilizes an inactive GDP-bound form through direct interactions with switch I and impairs the linker flexibility. Our studies provide a novel targeting site for the development of small molecules that selectively inhibit each Galpha subunit and an insight into the molecular mechanism of G protein activation.
-===Structure of heterotrimeric G protein Galpha-q beta gamma in complex with an inhibitor YM-254890===
+Structural basis for the specific inhibition of heterotrimeric Gq protein by a small molecule.,Nishimura A, Kitano K, Takasaki J, Taniguchi M, Mizuno N, Tago K, Hakoshima T, Itoh H Proc Natl Acad Sci U S A. 2010 Jul 16. PMID:20639466<ref>PMID:20639466</ref>
-{{ABSTRACT_PUBMED_20639466}}
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 3ah8" style="background-color:#fffaf0;"></div>
-==About this Structure==
+==See Also==
-[[3ah8]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus], [http://en.wikipedia.org/wiki/Chromobacterium_sp. Chromobacterium sp.] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3AH8 OCA].
+*[[Transducin 3D structures|Transducin 3D structures]]
+== References ==
-==Reference==
+<references/>
-<ref group="xtra">PMID:020639466</ref><references group="xtra"/>
+__TOC__
+</StructureSection>
 [[Category: Bos taurus]]
-[[Category: Chromobacterium sp.]]
+[[Category: Chromobacterium sp]]
+[[Category: Large Structures]]
 [[Category: Mus musculus]]
-[[Category: Hakoshima, T.]]
+[[Category: Rattus norvegicus]]
-[[Category: Itoh, H.]]
+[[Category: Hakoshima T]]
-[[Category: Kitano, K.]]
+[[Category: Itoh H]]
-[[Category: Mizuno, N.]]
+[[Category: Kitano K]]
-[[Category: Nishimura, A.]]
+[[Category: Mizuno N]]
-[[Category: Tago, K.]]
+[[Category: Nishimura A]]
-[[Category: Takasaki, J.]]
+[[Category: Tago K]]
-[[Category: Taniguchi, M.]]
+[[Category: Takasaki J]]
-[[Category: Galpha-q]]
+[[Category: Taniguchi M]]
-[[Category: Gbeta]]
-[[Category: Ggamma]]
-[[Category: Gtpase]]
-[[Category: Heterotrimeric g protein]]
-[[Category: Inhibitor]]
-[[Category: Signaling protein]]
-[[Category: Signaling protein-inhibitor complex]]
-[[Category: Ym-254890]]

3ah8

From Proteopedia

Current revision

Structure of heterotrimeric G protein Galpha-q beta gamma in complex with an inhibitor YM-254890

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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