RT Journal Article
SR Electronic
T1 Structural Mimicry in G Protein-Coupled Receptors: Implications of the High-Resolution Structure of Rhodopsin for Structure-Function Analysis of Rhodopsin-Like Receptors
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1
OP 19
DO 10.1124/mol.60.1.1
VO 60
IS 1
A1 Ballesteros, Juan A.
A1 Shi, Lei
A1 Javitch, Jonathan A.
YR 2001
UL http://molpharm.aspetjournals.org/content/60/1/1.abstract
AB The availability of a high-resolution structure of rhodopsin now allows us to reconsider research attempts to understand structure-function relationships in other G protein-coupled receptors (GPCRs). A comparison of the rhodopsin structure with the results of previous sequence analysis and molecular modeling that incorporated experimental results demonstrates a high degree of success for these methods in predicting the helix ends and protein-protein interface of GPCRs. Moreover, the amino acid residues inferred to form the surface of the binding-site crevice based on our application of the substituted-cysteine accessibility method in the dopamine D2 receptor are in remarkable agreement with the rhodopsin structure, with the notable exception of some residues in the fourth transmembrane segment. Based on our analysis of the data reviewed, we propose that the overall structures of rhodopsin and of amine receptors are very similar, although we also identified localized regions where the structure of these receptors may diverge. We further propose that several of the highly unusual structural features of rhodopsin are also present in amine GPCRs, despite the absence of amino acids that might have thought to have been critical to the adoption of these features. Thus, different amino acids or alternate microdomains can support similar deviations from regular α-helical structure, thereby resulting in similar tertiary structure. Such structural mimicry is a mechanism by which a common ancestor could diverge sufficiently to develop the selectivity necessary to interact with diverse signals, while still maintaining a similar overall fold. Through this process, the core function of signaling activation through a conformational change in the transmembrane segments that alters the conformation of the cytoplasmic surface and subsequent interaction with G proteins is presumably shared by the entire Class A family of receptors, despite their selectivity for a diverse group of ligands. GPCRsG protein coupled receptorsTMtransmembrane segmentSASAsolvent accessible surface areaSCAMsubstituted-cysteine accessibility methodMTSmethanethiosulfonateRMSDroot mean square distanceIpBABCp-(bromoacetamido)benzyl-1-[125I]iodocarazololE2second extracellular loopMDmolecular dynamics. Receptor abbreviations: 5H1A (5H1B, 5H2A), 5-hydroxytryptamine 1A (1B, 2A) receptorA1AA (A1ABA2AA), α1A (1B, 2A) adrenergic receptorAA1R (AA2A)adenosine A1 (A2A) receptorACM1 (ACM2ACM3, ACM5), muscarinic acetylcholine M1 (M2, M3, M5) receptorACTRadrenocorticotropin receptorAG2Rtype-1 angiotensin II receptorB2ARβ2 adrenergic receptorD2DRdopamine D2 receptorETBRendothelin B receptorET1Rendothelin-1 receptorGASRgastrin/cholecystokinin type B receptorGRHRgonadotropin-releasing hormone receptorHH2Rhistamine H2 receptorMSHRmelanocyte stimulating hormone receptorNK1Rsubstance-P receptorNK2Rsubstance-K receptorNTR1neurotensin type I receptorOPRKκ-type opioid receptorOPSDrhodopsinP2URP2U purinoceptor 1P2YRP2Y purinoceptor 1PAFRplatelet activating factor receptorTSHRthyrotropin receptor