Sandbox 173: Difference between revisions

As this ligand is bound in the 12-s-''trans'' conformation, there arises the non-bonding interactions between the C-13 methyl group and C-10 hydrogen that contribute to non-planarity. This leads to the ability of the chromophore polyene tail to undergo fast photoisomerization around the C-11=C-12 double bond during light-induced activation<ref>Article 2</ref>. Also, it is found that the C-11=C-12 double bond is pre-twisted in the ground state of rhodopsin, which is partly attributed to the C20 methyl group attached to C13 through interaction with Tryptophan 265. This pre-twist may give insight on the features of isomerization about this bond upon light activation <ref>Original article</ref>.

Somewhat enclosing this chromophore is a retinal binding pocket partially formed by the N-terminal domain overlaying the extracellular turns including Extracellular Helix 2, which folds into the molecular center<ref>Article 6</ref>.

==Function==

===Visual Signal Transduction===

====Photoisomeration of 11-''cis'' Retinal====

The 11-''cis'' retinal (retinylidene) Schiff base functions as an inverse agonist and is prominently involved in the activation of rhodopsin. The primary step in rhodopsin photoactivation occurs in the photoisomeration of rhodopsin, as light energy absorbed from a photon is converted into chemical energy, As a photon is absorbed by the retina, the 11-''cis'' retinylidene ligand is switched into an all-''trans'' retinal configuration<ref>Article 2</ref>. In this extremely efficient <200 fs process, the protein-binding pocket, initially fitted to accommodate the 11-''cis'' conformation of the chromophore, is preserved, which restrains the relaxation of the chromophore. The strained relaxation of conformational energy changes the protein state into the active form<ref>Article 2</ref>.

There is positive enthalpy associated with the formation of Metarhodopsin II. This formation of the active state, also linked with the increase in entropy, is suggested to release the constraints in the helices and expose the cytoplasmic binding sites<ref>Article 9</ref>. An important part of this process includes the 9-methyl group of retinal, which is suggested to provide a scaffold for proton transfers essential for the formation of the active state<ref>Article 9</ref>.

====Signalling Cascade and Polarization of the Cell Membrane====

The excited rhodopsin interacts with a large number of transducin molecules, found in the cytoplasic face of the disk membrane. Transducin is a member of the heterotrimeric GTP-binding proteins family, and it binds to GDP in the dark. This interaction generates a signaling cascade where transducin molecules are activated through the trigger of GDP-GTP nucleotide exchange in the α subunit<ref>Article 6</ref>.  Each activated transducin dissociates into Tα-GTP and Tβγ subunits, and Tα-GTP activates cGMP-specific phosphodiesterase by binding and removing its inhibitory subunit<ref>Textbook</ref>.  

Altogether, the different states of rhodopsin which include the short-lived, photo-rhodopsin, batho-rhodopsin, and lumi-rhodopsin, and longer-lived meta-rhodopsins give information about the structural status of the molecule during activation<ref>Article 9</ref>.

==Opsin==

===Topology Overview===

The overall dimeric structure of opsin is similar to rhodopsin, with seven transmembrane helices linked by three extracellular loops and three cytoplasmic loops and a cytoplasmic Helix 8. The small differences between the topology of the two proteins include a short helical turn in the cytoplasmic loop 1 in opsin, 1.5-2.5 helical turns longer in Helix 5 for opsin in comparison to rhodopsin, and a large outward tilt of Helix 6 of opsin<ref>Article Opsin 2</ref>. Also, in constrast to rhodopsin, opsin has two openings of the retinal-binding pocket; one of the openings is between Helix 1 and Helix 7, and the other opening is between the extracellular ends of Helix 5 and 6. This opening is formed by the residues <scene name='Sandbox_173/Opsin_retinal_opening/1'>Isoleucine 205 and Phenylalanine 208 in Helix 5, and by the residues Phenylalanine 273 and Phenylalanine 276 in Helix 6</scene><ref>Article Opsin 2</ref>. The two openings suggest different sites of retinal entrance and exit in retinal channeling<ref>Article Opsin 2</ref>.