4c7a

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of the Smoothened CRD, selenomethionine-labeled

Structural highlights

4c7a is a 2 chain structure with sequence from Danio rerio. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.3Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SMO_DANRE G protein-coupled receptor which associates with the patched protein (ptch) to transduce Hedgehog protein signaling. Binding of sonic hedgehog (shh) to its receptor patched prevents inhibition of smoothened (smo) by patched. When active, smo binds to and sequesters protein kinase A catalytic subunit prkaca at the cell membrane, preventing prkaca-mediated phosphorylation of gli transcription factors which releases the gli proteins from prkaca-mediated inhibition and allows for transcriptional activation of Hedgehog signaling pathway target genes (By similarity). Required for the development of primary and secondary motoneurons but not for the specification of midbrain dopaminergic neurons or development of the medial floor plate (PubMed:11493557). Required for induction of lateral floor plate and posterior motoneurons, anterior neural plate patterning, dorsoventral forebrain patterning, dorsoventral retinal patterning, optic stalk development, and formation of the forebrain primary axonal scaffold (PubMed:11566855). Required to regulate the formation of a subset of cerebellar neurons by limiting wnt1 expression which controls cerebellar expression of transcription factor olig2 (PubMed:18423594). Required for development of the pancreas (PubMed:34087472). Required for muscle development (PubMed:16136078). Required for the formation of a single continuous intestinal lumen from multiple discontinuous lumens, probably by regulating remodeling through rab11a-mediated trafficking to facilitate lumen fusion (PubMed:24504339). Required for development of the adenohypophysis (PubMed:11566855, PubMed:12606279). Required for anteroposterior patterning of the otic vesicle (PubMed:12588855). Required for development of the anterior craniofacial skeleton (PubMed:16481351). Required for patterning of the caudal fin (PubMed:17597528). Required during gastrulation and early somitogenesis stages to promote cardiomyocyte formation by regulating the specification of myocardial progenitors (PubMed:18842815). Required for induction of arterial endothelial cell formation by repressing venous cell fate (PubMed:20193674).[UniProtKB:P56726]^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12]

Publication Abstract from PubMed

The Hedgehog (Hh) signal is transduced across the membrane by the heptahelical protein Smoothened (Smo), a developmental regulator, oncoprotein and drug target in oncology. We present the 2.3 A crystal structure of the extracellular cysteine rich domain (CRD) of vertebrate Smo and show that it binds to oxysterols, endogenous lipids that activate Hh signaling. The oxysterol-binding groove in the Smo CRD is analogous to that used by Frizzled 8 to bind to the palmitoleyl group of Wnt ligands and to similar pockets used by other Frizzled-like CRDs to bind hydrophobic ligands. The CRD is required for signaling in response to native Hh ligands, showing that it is an important regulatory module for Smo activation. Indeed, targeting of the Smo CRD by oxysterol-inspired small molecules can block signaling by all known classes of Hh activators and by clinically relevant Smo mutants. DOI:http://dx.doi.org/10.7554/eLife.01340.001.

Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling.,Nachtergaele S, Whalen DM, Mydock LK, Zhao Z, Malinauskas T, Krishnan K, Ingham PW, Covey DF, Siebold C, Rohatgi R Elife. 2013 Oct 29;2:e01340. doi: 10.7554/eLife.01340. PMID:24171105^[13]

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

References

↑ Chen W, Burgess S, Hopkins N. Analysis of the zebrafish smoothened mutant reveals conserved and divergent functions of hedgehog activity. Development. 2001 Jun;128(12):2385-96. PMID:11493557 doi:10.1242/dev.128.12.2385
↑ Varga ZM, Amores A, Lewis KE, Yan YL, Postlethwait JH, Eisen JS, Westerfield M. Zebrafish smoothened functions in ventral neural tube specification and axon tract formation. Development. 2001 Sep;128(18):3497-509. PMID:11566855 doi:10.1242/dev.128.18.3497
↑ Hammond KL, Loynes HE, Folarin AA, Smith J, Whitfield TT. Hedgehog signalling is required for correct anteroposterior patterning of the zebrafish otic vesicle. Development. 2003 Apr;130(7):1403-17. PMID:12588855 doi:10.1242/dev.00360
↑ Sbrogna JL, Barresi MJ, Karlstrom RO. Multiple roles for Hedgehog signaling in zebrafish pituitary development. Dev Biol. 2003 Feb 1;254(1):19-35. PMID:12606279 doi:10.1016/s0012-1606(02)00027-1
↑ Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY, Reiter JF. Vertebrate Smoothened functions at the primary cilium. Nature. 2005 Oct 13;437(7061):1018-21. PMID:16136078 doi:10.1038/nature04117
↑ Eberhart JK, Swartz ME, Crump JG, Kimmel CB. Early Hedgehog signaling from neural to oral epithelium organizes anterior craniofacial development. Development. 2006 Mar;133(6):1069-77. PMID:16481351 doi:10.1242/dev.02281
↑ Hadzhiev Y, Lele Z, Schindler S, Wilson SW, Ahlberg P, Strähle U, Müller F. Hedgehog signaling patterns the outgrowth of unpaired skeletal appendages in zebrafish. BMC Dev Biol. 2007 Jun 27;7:75. PMID:17597528 doi:10.1186/1471-213X-7-75
↑ McFarland KA, Topczewska JM, Weidinger G, Dorsky RI, Appel B. Hh and Wnt signaling regulate formation of olig2+ neurons in the zebrafish cerebellum. Dev Biol. 2008 Jun 1;318(1):162-71. PMID:18423594 doi:10.1016/j.ydbio.2008.03.016
↑ Thomas NA, Koudijs M, van Eeden FJ, Joyner AL, Yelon D. Hedgehog signaling plays a cell-autonomous role in maximizing cardiac developmental potential. Development. 2008 Nov;135(22):3789-99. PMID:18842815 doi:10.1242/dev.024083
↑ Williams C, Kim SH, Ni TT, Mitchell L, Ro H, Penn JS, Baldwin SH, Solnica-Krezel L, Zhong TP. Hedgehog signaling induces arterial endothelial cell formation by repressing venous cell fate. Dev Biol. 2010 May 1;341(1):196-204. PMID:20193674 doi:10.1016/j.ydbio.2010.02.028
↑ Alvers AL, Ryan S, Scherz PJ, Huisken J, Bagnat M. Single continuous lumen formation in the zebrafish gut is mediated by smoothened-dependent tissue remodeling. Development. 2014 Mar;141(5):1110-9. PMID:24504339 doi:10.1242/dev.100313
↑ Korzh S, Winata CL, Gong Z, Korzh V. The development of zebrafish pancreas affected by deficiency of Hedgehog signaling. Gene Expr Patterns. 2021 Sep;41:119185. PMID:34087472 doi:10.1016/j.gep.2021.119185
↑ Nachtergaele S, Whalen DM, Mydock LK, Zhao Z, Malinauskas T, Krishnan K, Ingham PW, Covey DF, Siebold C, Rohatgi R. Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling. Elife. 2013 Oct 29;2:e01340. doi: 10.7554/eLife.01340. PMID:24171105 doi:http://dx.doi.org/10.7554/eLife.01340

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4c7a"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4c7a]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Danio_rerio Danio rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C7A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C7A FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.3&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=4c7a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c7a OCA], [https://pdbe.org/4c7a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c7a RCSB], [https://www.ebi.ac.uk/pdbsum/4c7a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c7a ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/Q90X26_DANRE Q90X26_DANRE]]
+[https://www.uniprot.org/uniprot/SMO_DANRE SMO_DANRE] G protein-coupled receptor which associates with the patched protein (ptch) to transduce Hedgehog protein signaling. Binding of sonic hedgehog (shh) to its receptor patched prevents inhibition of smoothened (smo) by patched. When active, smo binds to and sequesters protein kinase A catalytic subunit prkaca at the cell membrane, preventing prkaca-mediated phosphorylation of gli transcription factors which releases the gli proteins from prkaca-mediated inhibition and allows for transcriptional activation of Hedgehog signaling pathway target genes (By similarity). Required for the development of primary and secondary motoneurons but not for the specification of midbrain dopaminergic neurons or development of the medial floor plate (PubMed:11493557). Required for induction of lateral floor plate and posterior motoneurons, anterior neural plate patterning, dorsoventral forebrain patterning, dorsoventral retinal patterning, optic stalk development, and formation of the forebrain primary axonal scaffold (PubMed:11566855). Required to regulate the formation of a subset of cerebellar neurons by limiting wnt1 expression which controls cerebellar expression of transcription factor olig2 (PubMed:18423594). Required for development of the pancreas (PubMed:34087472). Required for muscle development (PubMed:16136078). Required for the formation of a single continuous intestinal lumen from multiple discontinuous lumens, probably by regulating remodeling through rab11a-mediated trafficking to facilitate lumen fusion (PubMed:24504339). Required for development of the adenohypophysis (PubMed:11566855, PubMed:12606279). Required for anteroposterior patterning of the otic vesicle (PubMed:12588855). Required for development of the anterior craniofacial skeleton (PubMed:16481351). Required for patterning of the caudal fin (PubMed:17597528). Required during gastrulation and early somitogenesis stages to promote cardiomyocyte formation by regulating the specification of myocardial progenitors (PubMed:18842815). Required for induction of arterial endothelial cell formation by repressing venous cell fate (PubMed:20193674).[UniProtKB:P56726]<ref>PMID:11493557</ref> <ref>PMID:11566855</ref> <ref>PMID:12588855</ref> <ref>PMID:12606279</ref> <ref>PMID:16136078</ref> <ref>PMID:16481351</ref> <ref>PMID:17597528</ref> <ref>PMID:18423594</ref> <ref>PMID:18842815</ref> <ref>PMID:20193674</ref> <ref>PMID:24504339</ref> <ref>PMID:34087472</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The Hedgehog (Hh) signal is transduced across the membrane by the heptahelical protein Smoothened (Smo), a developmental regulator, oncoprotein and drug target in oncology. We present the 2.3 A crystal structure of the extracellular cysteine rich domain (CRD) of vertebrate Smo and show that it binds to oxysterols, endogenous lipids that activate Hh signaling. The oxysterol-binding groove in the Smo CRD is analogous to that used by Frizzled 8 to bind to the palmitoleyl group of Wnt ligands and to similar pockets used by other Frizzled-like CRDs to bind hydrophobic ligands. The CRD is required for signaling in response to native Hh ligands, showing that it is an important regulatory module for Smo activation. Indeed, targeting of the Smo CRD by oxysterol-inspired small molecules can block signaling by all known classes of Hh activators and by clinically relevant Smo mutants. DOI:http://dx.doi.org/10.7554/eLife.01340.001.
+Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling.,Nachtergaele S, Whalen DM, Mydock LK, Zhao Z, Malinauskas T, Krishnan K, Ingham PW, Covey DF, Siebold C, Rohatgi R Elife. 2013 Oct 29;2:e01340. doi: 10.7554/eLife.01340. PMID:24171105<ref>PMID:24171105</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 4c7a" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>

4c7a

From Proteopedia

Current revision

Crystal structure of the Smoothened CRD, selenomethionine-labeled

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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