8thl

From Proteopedia

(Difference between revisions)

Current revision

Cryo-EM structure of epinephrine-bound alpha-1A-adrenergic receptor in complex with heterotrimeric Gq-protein

Structural highlights

8thl is a 5 chain structure with sequence from Escherichia virus T4 and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.1Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GNAS2_HUMAN Pseudopseudohypoparathyroidism;Pseudohypoparathyroidism type 1A;Progressive osseous heteroplasia;Polyostotic fibrous dysplasia;Monostotic fibrous dysplasia;Pseudohypoparathyroidism type 1C;Pseudohypoparathyroidism type 1B;McCune-Albright syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Most affected individuals have defects in methylation of the gene. In some cases microdeletions involving the STX16 appear to cause loss of methylation at exon A/B of GNAS, resulting in PHP1B. Paternal uniparental isodisomy have also been observed. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.GNAQ_HUMAN Sturge-Weber syndrome;Phakomatosis cesioflammea;Uveal melanoma;Familial multiple nevi flammei. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.

Function

GNAI2_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. May play a role in cell division.^[1] Isoform sGi2: Regulates the cell surface density of dopamine receptors DRD2 by sequestrating them as an intracellular pool.^[2] GNAS2_HUMAN Guanine nucleotide-binding proteins (G proteins) function as transducers in numerous signaling pathways controlled by G protein-coupled receptors (GPCRs) (PubMed:17110384). Signaling involves the activation of adenylyl cyclases, resulting in increased levels of the signaling molecule cAMP (PubMed:26206488, PubMed:8702665). GNAS functions downstream of several GPCRs, including beta-adrenergic receptors (PubMed:21488135). Stimulates the Ras signaling pathway via RAPGEF2 (PubMed:12391161).^[3] ^[4] ^[5] ^[6] ^[7] GNAQ_HUMAN 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) (By similarity).

Publication Abstract from PubMed

alpha(1)-adrenergic receptors (alpha(1)-ARs) play critical roles in the cardiovascular and nervous systems where they regulate blood pressure, cognition, and metabolism. However, the lack of specific agonists for all alpha(1) subtypes has limited our understanding of the physiological roles of different alpha(1)-AR subtypes, and led to the stagnancy in agonist-based drug development for these receptors. Here we report cryo-EM structures of alpha(1A)-AR in complex with heterotrimeric G-proteins and either the endogenous common agonist epinephrine or the alpha(1A)-AR-specific synthetic agonist A61603. These structures provide molecular insights into the mechanisms underlying the discrimination between alpha(1A)-AR and alpha(1B)-AR by A61603. Guided by the structures and corresponding molecular dynamics simulations, we engineer alpha(1A)-AR mutants that are not responsive to A61603, and alpha(1B)-AR mutants that can be potently activated by A61603. Together, these findings advance our understanding of the agonist specificity for alpha(1)-ARs at the molecular level, opening the possibility of rational design of subtype-specific agonists.

Structural basis of agonist specificity of alpha(1A)-adrenergic receptor.,Su M, Wang J, Xiang G, Do HN, Levitz J, Miao Y, Huang XY Nat Commun. 2023 Aug 10;14(1):4819. doi: 10.1038/s41467-023-40524-2. PMID:37563160^[8]

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

References

↑ 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
↑ Lopez-Aranda MF, Acevedo MJ, Gutierrez A, Koulen P, Khan ZU. Role of a Galphai2 protein splice variant in the formation of an intracellular dopamine D2 receptor pool. J Cell Sci. 2007 Jul 1;120(Pt 13):2171-8. Epub 2007 Jun 5. PMID:17550964 doi:http://dx.doi.org/jcs.005611
↑ Pak Y, Pham N, Rotin D. Direct binding of the beta1 adrenergic receptor to the cyclic AMP-dependent guanine nucleotide exchange factor CNrasGEF leads to Ras activation. Mol Cell Biol. 2002 Nov;22(22):7942-52. PMID:12391161
↑ Gao X, Sadana R, Dessauer CW, Patel TB. Conditional stimulation of type V and VI adenylyl cyclases by G protein betagamma subunits. J Biol Chem. 2007 Jan 5;282(1):294-302. Epub 2006 Nov 16. PMID:17110384 doi:http://dx.doi.org/10.1074/jbc.M607522200
↑ Thiele S, de Sanctis L, Werner R, Grotzinger J, Aydin C, Juppner H, Bastepe M, Hiort O. Functional characterization of GNAS mutations found in patients with pseudohypoparathyroidism type Ic defines a new subgroup of pseudohypoparathyroidism affecting selectively Gsalpha-receptor interaction. Hum Mutat. 2011 Jun;32(6):653-60. doi: 10.1002/humu.21489. Epub 2011 Apr 12. PMID:21488135 doi:http://dx.doi.org/10.1002/humu.21489
↑ Brand CS, Sadana R, Malik S, Smrcka AV, Dessauer CW. Adenylyl Cyclase 5 Regulation by Gbetagamma Involves Isoform-Specific Use of Multiple Interaction Sites. Mol Pharmacol. 2015 Oct;88(4):758-67. doi: 10.1124/mol.115.099556. Epub 2015 Jul , 23. PMID:26206488 doi:http://dx.doi.org/10.1124/mol.115.099556
↑ Farfel Z, Iiri T, Shapira H, Roitman A, Mouallem M, Bourne HR. Pseudohypoparathyroidism, a novel mutation in the betagamma-contact region of Gsalpha impairs receptor stimulation. J Biol Chem. 1996 Aug 16;271(33):19653-5. PMID:8702665
↑ Su M, Wang J, Xiang G, Do HN, Levitz J, Miao Y, Huang XY. Structural basis of agonist specificity of α(1A)-adrenergic receptor. Nat Commun. 2023 Aug 10;14(1):4819. PMID:37563160 doi:10.1038/s41467-023-40524-2

1 Structural highlights
2 Disease
3 Function
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/8thl"

Categories: Escherichia virus T4 | Homo sapiens | Large Structures | Huang XY | Su M

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8thl is ON HOLD
+==Cryo-EM structure of epinephrine-bound alpha-1A-adrenergic receptor in complex with heterotrimeric Gq-protein==
+<StructureSection load='8thl' size='340' side='right'caption='[[8thl]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8thl]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_virus_T4 Escherichia virus T4] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8THL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8THL FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.1&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ALE:L-EPINEPHRINE'>ALE</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=8thl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8thl OCA], [https://pdbe.org/8thl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8thl RCSB], [https://www.ebi.ac.uk/pdbsum/8thl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8thl ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/GNAS2_HUMAN GNAS2_HUMAN] Pseudopseudohypoparathyroidism;Pseudohypoparathyroidism type 1A;Progressive osseous heteroplasia;Polyostotic fibrous dysplasia;Monostotic fibrous dysplasia;Pseudohypoparathyroidism type 1C;Pseudohypoparathyroidism type 1B;McCune-Albright syndrome. The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry. Most affected individuals have defects in methylation of the gene. In some cases microdeletions involving the STX16 appear to cause loss of methylation at exon A/B of GNAS, resulting in PHP1B. Paternal uniparental isodisomy have also been observed.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.[https://www.uniprot.org/uniprot/GNAQ_HUMAN GNAQ_HUMAN] Sturge-Weber syndrome;Phakomatosis cesioflammea;Uveal melanoma;Familial multiple nevi flammei. The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.
+== Function ==
+[https://www.uniprot.org/uniprot/GNAI2_HUMAN GNAI2_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. May play a role in cell division.<ref>PMID:17635935</ref>   Isoform sGi2: Regulates the cell surface density of dopamine receptors DRD2 by sequestrating them as an intracellular pool.<ref>PMID:17550964</ref> [https://www.uniprot.org/uniprot/GNAS2_HUMAN GNAS2_HUMAN] Guanine nucleotide-binding proteins (G proteins) function as transducers in numerous signaling pathways controlled by G protein-coupled receptors (GPCRs) (PubMed:17110384). Signaling involves the activation of adenylyl cyclases, resulting in increased levels of the signaling molecule cAMP (PubMed:26206488, PubMed:8702665). GNAS functions downstream of several GPCRs, including beta-adrenergic receptors (PubMed:21488135). Stimulates the Ras signaling pathway via RAPGEF2 (PubMed:12391161).<ref>PMID:12391161</ref> <ref>PMID:17110384</ref> <ref>PMID:21488135</ref> <ref>PMID:26206488</ref> <ref>PMID:8702665</ref> [https://www.uniprot.org/uniprot/GNAQ_HUMAN GNAQ_HUMAN] 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) (By similarity).
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+alpha(1)-adrenergic receptors (alpha(1)-ARs) play critical roles in the cardiovascular and nervous systems where they regulate blood pressure, cognition, and metabolism. However, the lack of specific agonists for all alpha(1) subtypes has limited our understanding of the physiological roles of different alpha(1)-AR subtypes, and led to the stagnancy in agonist-based drug development for these receptors. Here we report cryo-EM structures of alpha(1A)-AR in complex with heterotrimeric G-proteins and either the endogenous common agonist epinephrine or the alpha(1A)-AR-specific synthetic agonist A61603. These structures provide molecular insights into the mechanisms underlying the discrimination between alpha(1A)-AR and alpha(1B)-AR by A61603. Guided by the structures and corresponding molecular dynamics simulations, we engineer alpha(1A)-AR mutants that are not responsive to A61603, and alpha(1B)-AR mutants that can be potently activated by A61603. Together, these findings advance our understanding of the agonist specificity for alpha(1)-ARs at the molecular level, opening the possibility of rational design of subtype-specific agonists.
-Authors:
+Structural basis of agonist specificity of alpha(1A)-adrenergic receptor.,Su M, Wang J, Xiang G, Do HN, Levitz J, Miao Y, Huang XY Nat Commun. 2023 Aug 10;14(1):4819. doi: 10.1038/s41467-023-40524-2. PMID:37563160<ref>PMID:37563160</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 8thl" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Transducin 3D structures|Transducin 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Escherichia virus T4]]
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Huang XY]]
+[[Category: Su M]]

8thl

From Proteopedia

Current revision

Cryo-EM structure of epinephrine-bound alpha-1A-adrenergic receptor in complex with heterotrimeric Gq-protein

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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