Sandbox 173

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Revision as of 04:47, 28 March 2010

spinqualitylabelsall models PDB ID 1u19 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
1u19, resolution 2.20Å ()
Ligands:	, , , , , , , ,
Non-Standard Residues:
Related:	1f88, 1hzx, 1l9h
Structural annotation: Resources: CATH : 1U19A00, 1U19B00 UniProt : P02699
Evolutionary conservation: Toggle Conservation Colors: Rows = identical sequences: Further Information: Caveats, Explanation, Complete Results at ConSurfDB
Resources:	FirstGlance, OCA, PDBsum, RCSB
Coordinates:	save as pdb, mmCIF, xml

Introduction

Rhodopsin

Rhodopsin, a dimeric protein, is a highly characterized G protein-coupled receptor found in membranous disks of the outer segments of rod and cone cells. It is part of the superfamily of G protein-coupled receptors that mediate responses to visual, olfactory, hormonal, and neurotransmitter signals among others^[1]. Rhodopsin is involved in visual transduction and the visual system in classic G protein-coupled receptor mechanisms^[2].

G Protein-Coupled Receptors

Rhodopsin is a member of the superfamily of G protein-coupled receptors which incorporate the activation of G proteins in their mediation of signalling and intracellular actions. Rhodopsin shares similar membrane topology with the members of the superfamily (Family A of the G protein-coupled receptors) which include the seven transmembrane helices, an extracellular N terminus and cytoplasmic C terminus^[3]. The seven-helical pattern is found from archaebacteria (specifically studied is bacteriorhodopsin) to humans, both which share the same retinylidene chromophore as well ^[4]. As the crystal structure for any G protein-coupled receptor with the seven transmembrane domain has only been solved for rhodopsin, rhodopsin may be a reference for the structure and function relationship for other G protein-coupled receptors^[5]. Like most G protein-coupled receptors, the activated rhodopsin catalyzes uptake of GTP by the heterotrimeric G protein, in this case transducin, which interacts with the cytoplasmic loops of the receptor^[6]. However, the covalent binding nature of rhodopsin to its retinal ligand is unlike most G protein-coupled receptors. As well, another difference of rhodopsin from the members of this superfamily relates to light as the inducer for activation^[7].

Structure

Rhodopsin Architecture

Rhodopsin consists of seven mostly α-helical transmembrane domains (H1-H7) linked sequentially by extracellular and cytoplasmic loops (E1-E3 and C1-C3 respectively), with the extracellular amino-terminal tail and the cytoplasmic carboxyl-terminal tail^[8]. Four of the helices are tilted and three of the helices are approximately perpendicular to the membrane plane^[9]. There is notable interaction between the four extracellular domains, but only a few associations are observed with the cytoplasmic domains^[10]. Helix 7 is close to being elongated around the Lysine 296 retinal attachment site, and also contains the residues Proline 291 and Proline 303, with Proline 303 being part of a conserved motif^[11]. Near the retinal region, there is a β4 strand (Serine 186-Cysteine 187-Glycine 188-Isoleucine 189) within the Extracellular Helix 2 that runs almost parallel to the chromophore held in place, and is stabilized by the essential conserved disulfide bond between Cysteine 110 and Cysteine 187. This loop also potentially contacts the chromophore through Glutamine 181 and Tyrosine 191^[12]. Water molecules are observed to be located in the extracellular domains of rhodopsin; specifically, the water molecules around the second extracellular loop between Helix 4 and 5 solvate the loop when the loop interacts with the retinal chromophore and possibly contribute to its flexibility if rearrangement occurs^[13].

There is the presence of a cationic amphipathic Helix 8, known as the fourth cytoplasmic loop, that spans from Asparagine 310 to Cysteine 323 and is formed from the C-terminal tail anchoring to the membrane by two cysteines (Cys322 and Cys323), which include palmitates in the structure. This helix runs approximately parallel to the cytoplasmic surface and is involved in Gtγ binding^[14], as well as the modulation of rhodopsin-transducin interactions and rhodopsin-phospholipid interactions^[15].

The protonated Schiff base of rhodopsin is stabilized through Glutamine 113 residue electrostatic interaction with the counterion, holding the inactive rhodopsin in its state^[16]. A metal zinc ion bridge chelated by histidine side-chains and connected to the cytoplasmic ends of Helix 3 and 6 is observed to prevent receptor activation. This perhaps indicates that separation of these cytoplasmic ends would contribute to rhodopsin activation^[17]. The structure of rhodopsin may provide stability to the important Schiff base linkage with the retinal by affecting its hydrolysis, limiting its interactions with solvent, inhibiting its release when hydrolyzed, thus encouraging rebinding of the Schiff base linkage^[18].

Retinal Chromophore of Rhodospin

Rhodopsin consists of an opsin apoprotein and a in its active site. Rhodopsin is bound covalently to the 11-cis retinal, the chromophore or "ligand," (shown in yellow) and this retinal is found in deeply in the core of the helices, in a hydrophobic site, parallel to the lipid bilayer^[19]. Comparatively, it is situated more towards the extracellular planes of the membrane bilayer ^[20]. The retinal is attached in the active site of rhodopsin through a protonated Schiff base (an N-substituted imine) bond to the ε-amino group of Lysine 296 residue (shown in green) on the C-terminal Helix 7, with this linkage creating a positive charge on the chromophore ^[21].

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^[22]. 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 ^[23]. 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^[24]. The retinal protonated Schiff base and Glutamine 113 efficiently locks the receptor in an inactive state in the dark^[25].

Function

Visual Signal Transduction and Termination

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^[26]. In this 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^[27].

Opsin

Opsin is the aproprotein that activates trandsducin. The all-trans retinal conformation enhances opsin activity on transducin. Opsin is covalently bound to the retinal chromophore by a protonated Schiff base^[28].

References

• Okada T, Sugihara M, Bondar AN, Elstner M, Entel P, Buss V. The retinal conformation and its environment in rhodopsin in light of a new 2.2 A crystal structure. J Mol Biol. 2004 Sep 10;342(2):571-83. PMID:15327956 doi:10.1016/j.jmb.2004.07.044

1. ↑ Article 1
2. ↑ Article 12
3. ↑ Article 20
4. ↑ Article 12
5. ↑ Article 20
6. ↑ Article 10
7. ↑ Article 20
8. ↑ Article 12
9. ↑ Article 4
10. ↑ Article 9
11. ↑ Article 9
12. ↑ Article 12
13. ↑ Original article
14. ↑ Article 9
15. ↑ Article 12
16. ↑ Article 20
17. ↑ Article 10
18. ↑ Article 3
19. ↑ Article 19
20. ↑ Article 12
21. ↑ Article 4
22. ↑ Article 2
23. ↑ Original article
24. ↑ Article 6
25. ↑ Article 4
26. ↑ Article 2
27. ↑ Article 2
28. ↑ Article 21