6ot0

From Proteopedia

(Difference between revisions)

Current revision

Structure of human Smoothened-Gi complex

6ot0, resolution 3.90Å

Structural highlights

6ot0 is a 6 chain structure with sequence from Human and Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	SMO, SMOH (HUMAN), GNAI1 (HUMAN), GNB1 (HUMAN), GNG2 (HUMAN)
Experimental data:	Check to display Experimental Data
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[GBG2_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity). [SMO_HUMAN] G protein-coupled receptor that probably associates with the patched protein (PTCH) to transduce the hedgehog's proteins signal. Binding of sonic hedgehog (SHH) to its receptor patched is thought to prevent normal inhibition by patched of smoothened (SMO). Required for the accumulation of KIF7 and GLI3 in the cilia.^[1] [GBB1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.^[2] [GNAI1_HUMAN] 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] ^[4]

Publication Abstract from PubMed

The oncoprotein Smoothened (SMO), a G-protein-coupled receptor (GPCR) of the Frizzled-class (class-F), transduces the Hedgehog signal from the tumour suppressor Patched-1 (PTCH1) to the glioma-associated-oncogene (GLI) transcription factors, which activates the Hedgehog signalling pathway(1,2). It has remained unknown how PTCH1 modulates SMO, how SMO is stimulated to form a complex with heterotrimeric G proteins and whether G-protein coupling contributes to the activation of GLI proteins(3). Here we show that 24,25-epoxycholesterol, which we identify as an endogenous ligand of PTCH1, can stimulate Hedgehog signalling in cells and can trigger G-protein signalling via human SMO in vitro. We present a cryo-electron microscopy structure of human SMO bound to 24(S),25-epoxycholesterol and coupled to a heterotrimeric Gi protein. The structure reveals a ligand-binding site for 24(S),25-epoxycholesterol in the 7-transmembrane region, as well as a Gi-coupled activation mechanism of human SMO. Notably, the Gi protein presents a different arrangement from that of class-A GPCR-Gi complexes. Our work provides molecular insights into Hedgehog signal transduction and the activation of a class-F GPCR.

Cryo-EM structure of oxysterol-bound human Smoothened coupled to a heterotrimeric Gi.,Qi X, Liu H, Thompson B, McDonald J, Zhang C, Li X Nature. 2019 Jun 5. pii: 10.1038/s41586-019-1286-0. doi:, 10.1038/s41586-019-1286-0. PMID:31168089^[5]

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

References

↑ Endoh-Yamagami S, Evangelista M, Wilson D, Wen X, Theunissen JW, Phamluong K, Davis M, Scales SJ, Solloway MJ, de Sauvage FJ, Peterson AS. The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development. Curr Biol. 2009 Aug 11;19(15):1320-6. doi: 10.1016/j.cub.2009.06.046. Epub 2009, Jul 9. PMID:19592253 doi:http://dx.doi.org/10.1016/j.cub.2009.06.046
↑ Johnston CA, Kimple AJ, Giguere PM, Siderovski DP. Structure of the parathyroid hormone receptor C terminus bound to the G-protein dimer Gbeta1gamma2. Structure. 2008 Jul;16(7):1086-94. PMID:18611381 doi:http://dx.doi.org/10.1016/j.str.2008.04.010
↑ Cho H, Kehrl JH. Localization of Gi alpha proteins in the centrosomes and at the midbody: implication for their role in cell division. J Cell Biol. 2007 Jul 16;178(2):245-55. PMID:17635935 doi:10.1083/jcb.200604114
↑ Johnston CA, Siderovski DP. Structural basis for nucleotide exchange on G alpha i subunits and receptor coupling specificity. Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):2001-6. Epub 2007 Jan 30. PMID:17264214
↑ Qi X, Liu H, Thompson B, McDonald J, Zhang C, Li X. Cryo-EM structure of oxysterol-bound human Smoothened coupled to a heterotrimeric Gi. Nature. 2019 Jun 5. pii: 10.1038/s41586-019-1286-0. doi:, 10.1038/s41586-019-1286-0. PMID:31168089 doi:http://dx.doi.org/10.1038/s41586-019-1286-0

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6ot0"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6ot0 is ON HOLD
+==Structure of human Smoothened-Gi complex==
+<SX load='6ot0' size='340' side='right' viewer='molstar' caption='[[6ot0]], [[Resolution|resolution]] 3.90&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6ot0]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OT0 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6OT0 FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CO1:17-[3-(3,3-DIMETHYL-OXIRANYL)-1-METHYL-PROPYL]-10,13-DIMETHYL-2,3,4,7,8,9,10,11,12,13,14,15,16,17-TETRADECAHYDRO-1H-CYCLOPENTA[A]PHENANTHREN-3-OL'>CO1</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SMO, SMOH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GNAI1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GNB1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GNG2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6ot0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ot0 OCA], [http://pdbe.org/6ot0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ot0 RCSB], [http://www.ebi.ac.uk/pdbsum/6ot0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ot0 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/GBG2_HUMAN GBG2_HUMAN]] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity). [[http://www.uniprot.org/uniprot/SMO_HUMAN SMO_HUMAN]] G protein-coupled receptor that probably associates with the patched protein (PTCH) to transduce the hedgehog's proteins signal. Binding of sonic hedgehog (SHH) to its receptor patched is thought to prevent normal inhibition by patched of smoothened (SMO). Required for the accumulation of KIF7 and GLI3 in the cilia.<ref>PMID:19592253</ref>  [[http://www.uniprot.org/uniprot/GBB1_HUMAN GBB1_HUMAN]] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.<ref>PMID:18611381</ref>  [[http://www.uniprot.org/uniprot/GNAI1_HUMAN GNAI1_HUMAN]] 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:17635935</ref> <ref>PMID:17264214</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The oncoprotein Smoothened (SMO), a G-protein-coupled receptor (GPCR) of the Frizzled-class (class-F), transduces the Hedgehog signal from the tumour suppressor Patched-1 (PTCH1) to the glioma-associated-oncogene (GLI) transcription factors, which activates the Hedgehog signalling pathway(1,2). It has remained unknown how PTCH1 modulates SMO, how SMO is stimulated to form a complex with heterotrimeric G proteins and whether G-protein coupling contributes to the activation of GLI proteins(3). Here we show that 24,25-epoxycholesterol, which we identify as an endogenous ligand of PTCH1, can stimulate Hedgehog signalling in cells and can trigger G-protein signalling via human SMO in vitro. We present a cryo-electron microscopy structure of human SMO bound to 24(S),25-epoxycholesterol and coupled to a heterotrimeric Gi protein. The structure reveals a ligand-binding site for 24(S),25-epoxycholesterol in the 7-transmembrane region, as well as a Gi-coupled activation mechanism of human SMO. Notably, the Gi protein presents a different arrangement from that of class-A GPCR-Gi complexes. Our work provides molecular insights into Hedgehog signal transduction and the activation of a class-F GPCR.
-Authors:
+Cryo-EM structure of oxysterol-bound human Smoothened coupled to a heterotrimeric Gi.,Qi X, Liu H, Thompson B, McDonald J, Zhang C, Li X Nature. 2019 Jun 5. pii: 10.1038/s41586-019-1286-0. doi:, 10.1038/s41586-019-1286-0. PMID:31168089<ref>PMID:31168089</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6ot0" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Transducin 3D structures|Transducin 3D structures]]
+== References ==
+<references/>
+__TOC__
+</SX>
+[[Category: Human]]
+[[Category: Large Structures]]
+[[Category: Lk3 transgenic mice]]
+[[Category: Li, X]]
+[[Category: Qi, X]]
+[[Category: Complex]]
+[[Category: Gpcr]]
+[[Category: Hedgehog signaling]]
+[[Category: Signaling protein]]

6ot0

From Proteopedia

Current revision

Structure of human Smoothened-Gi complex

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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