Beta2 adrenergic receptor-Gs protein complex: Difference between revisions
No edit summary |
No edit summary |
||
| Line 8: | Line 8: | ||
== Complex structure == | == Complex structure == | ||
The overall structure shows the | The overall structure shows the β2AR (dark blue) bound to an agonist (in spheres) along with a T4 lysozyme fused to its amino terminus in order to facilitate crystallization. The receptor interacts with Gαs (light blue). Gαs together with Gβ (light green) and Gγ (gold) constitute the heterotrimeric G protein Gs. A Gs-binding nanobody which also facilitates crystallization (pink) binds the G protein between the a and b subunits. | ||
== G-Protein-GPCR Intercations == | == G-Protein-GPCR Intercations == | ||
The | The α5-helix of Gαs docks into a cavity formed on the intracellular side of the receptor by the opening of transmembrane helices 5 and 6. Within the transmembrane core, the interactions are primarily non-polar - an exception involves <scene name='70/701430/Receptor_g_protein_interaction/4'>packing of Tyr 391 of the α5-helix against Arg 131 of the conserved DRY sequence in TM3. Arg 131 also packs against Tyr 326 of the conserved NPxxY sequence in TM7</scene>. As the α5-helix exits the receptor it forms a network of polar interactions with TM5 and TM3. Receptor residues <scene name='70/701430/Receptor_gprotein_interaction2/1'>Thr 68 and Asp 130 interact with the ICL2 helix of the β2AR via Tyr 141, positioning the helix so that Phe 139 of the receptor docks into a hydrophobic pocket on the G protein surface</scene>, thereby structurally linking receptor–G protein interactions with the highly conserved DRY motif of the β2AR. | ||
== G-Protein Cycle == | == G-Protein Cycle == | ||
[[Image:ImgSmall1.jpg|500px|G protein cycle for the | [[Image:ImgSmall1.jpg|500px|G protein cycle for the β2AR–Gs complex. Reprinted by permission from Macmillan Publishers Ltd on behalf of Cancer Research UK: Nature 477, 549–555, copyright 2011]] | ||
The figure shows the G Protein cycle <ref>doi:10.1038/nature10361</ref> - an extracellular agonist binding to the β2AR leads <scene name='70/701430/Receptor_morphing_animation/2'>to conformational rearrangements of the cytoplasmic ends of transmembrane segments</scene> that enable the Gs heterotrimer to bind the receptor. GDP is released from the α subunit upon formation of β2AR–Gs complex. The GTP binds to the nucleotide-free α subunit resulting in dissociation of the α and βγ subunits from the receptor. The subunits regulate their respective effector proteins adenylyl cyclase (AC) and Ca2+ channels. The Gs heterotrimer reassembles from α and βγ subunits following hydrolysis of GTP to GDP in the α subunit. | The figure shows the G Protein cycle <ref>doi:10.1038/nature10361</ref> - an extracellular agonist binding to the β2AR leads <scene name='70/701430/Receptor_morphing_animation/2'>to conformational rearrangements of the cytoplasmic ends of transmembrane segments</scene> that enable the Gs heterotrimer to bind the receptor. GDP is released from the α subunit upon formation of β2AR–Gs complex. The GTP binds to the nucleotide-free α subunit resulting in dissociation of the α and βγ subunits from the receptor. The subunits regulate their respective effector proteins adenylyl cyclase (AC) and Ca2+ channels. The Gs heterotrimer reassembles from α and βγ subunits following hydrolysis of GTP to GDP in the α subunit. | ||
| Line 20: | Line 20: | ||
== G-Protein variability == | == G-Protein variability == | ||
The Gαs subunit consists of two domains, the Ras domain (αRas) and the α-helical domain (αAH). Both are involved in nucleotide binding. A big discovery made thanks to this structure is that the | The Gαs subunit consists of two domains, the Ras domain (αRas) and the α-helical domain (αAH). Both are involved in nucleotide binding. A big discovery made thanks to this structure is that the Gα subunit has large variability between its GTP bound (active) and nucleotide free states, where <scene name='70/701430/Gamorph/2'>the αAH domain has a variable position relative to the αRas domain</scene> | ||
==See Also== | ==See Also== | ||