+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Analysis of full and partial agonists binding to beta2-adrenergic receptor suggests a role of transmembrane helix V in agonist-specific conformational changes



Analysis of full and partial agonists binding to beta2-adrenergic receptor suggests a role of transmembrane helix V in agonist-specific conformational changes



Journal of Molecular Recognition 22(4): 307-318



The 2.4 A crystal structure of the beta(2)-adrenergic receptor (beta(2)AR) in complex with the high-affinity inverse agonist (-)-carazolol provides a detailed structural framework for the analysis of ligand recognition by adrenergic receptors. Insights into agonist binding and the corresponding conformational changes triggering G-protein coupled receptor (GPCR) activation mechanism are of special interest. Here we show that while the carazolol pocket captured in the beta(2)AR crystal structure accommodates (-)-isoproterenol and other agonists without steric clashes, a finite movement of the flexible extracellular part of TM-V helix (TM-Ve) obtained by receptor optimization in the presence of docked ligand can further improve the calculated binding affinities for agonist compounds. Tilting of TM-Ve towards the receptor axis provides a more complete description of polar receptor-ligand interactions for full and partial agonists, by enabling optimal engagement of agonists with two experimentally identified anchor sites, formed by Asp113/Asn312 and Ser203/Ser204/Ser207 side chains. Further, receptor models incorporating a flexible TM-V backbone allow reliable prediction of binding affinities for a set of diverse ligands, suggesting potential utility of this approach to design of effective and subtype-specific agonists for adrenergic receptors. Systematic differences in capacity of partial, full and inverse agonists to induce TM-V helix tilt in the beta(2)AR model suggest potential role of TM-V as a conformational "rheostat" involved in the whole spectrum of beta(2)AR responses to small molecule signals.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 051522669

Download citation: RISBibTeXText

PMID: 19353579

DOI: 10.1002/jmr.949


Related references

beta2-adrenergic receptor desensitization, internalization, and phosphorylation in response to full and partial agonists. Journal of Biological Chemistry 272(38): 23871-9, 1997

Site-selective fluorescent labeling of the beta2 adrenergic receptor Mapping agonist-induced conformational changes at the cytoplasmic side of transmembrane segment VI. Society for Neuroscience Abstracts 24(1-2): 24, 1998

Selective structure-based virtual screening for full and partial agonists of the beta2 adrenergic receptor. Journal of Medicinal Chemistry 51(16): 4978-4985, 2008

Beta 2 -adrenergic receptor homodimers: Role of transmembrane domain 1 and helix 8 in dimerization and cell surface expression. Biochimica et Biophysica Acta. Biomembranes 1859(9 Pt A): 1445-1455, 2017

Activation Pathways of Agonists, Partial Agonists and Inverse Agonist in Beta1 and Beta2 Adrenergic Receptors. Biophysical Journal 98(3): 646a-647a, 2010

The role of transmembrane helix 5 in agonist binding to the human H3 receptor. Journal of Pharmacology and Experimental Therapeutics 301(2): 451-458, 2002

Alpha 1 adrenergic receptor binding and efficacy of full and partial agonist. FASEB Journal 4(3): A603, 1990

Relationship between G-protein activation and alpha-2-D adrenergic receptor binding for full and partial agonists. FASEB Journal 7(3-4): A599, 1993

Agonist-induced conformational changes in the beta2 adrenergic receptor. Journal of Peptide Research 60(6): 317-321, 2002

The stability of the agonist beta2-adrenergic receptor-Gs complex: evidence for agonist-specific states. Molecular Pharmacology 52(1): 144-154, 1997

Conversion of partial alpha2-adrenergic receptor agonists of full agonists by altering the population of G proteins expressed in a cell. FASEB Journal 12(4): A455, 1998

Role of Lys324 in helix VI of the human beta1-adrenergic receptor in imparting high-affinity agonist binding characteristics. FASEB Journal 17(4-5): Abstract No 142 2, 2003

Reconstitution of partial reactions requiring the beta-adrenergic receptor and the specific response to binding of the agonist. Advances in Cyclic Nucleotide and Protein Phosphorylation Research 17: 29-35, 1984

Mutation of a conserved aspartic acid in the beta2 adrenergic receptor Constitutive activation, structural instability, and conformational rearrangement of helix VI. Society for Neuroscience Abstracts 24(1-2): 23, 1998

Weak partial agonists target beta2-adrenergic receptors to lysosomes without rapid receptor endocytosis. Molecular Biology of the Cell 9(Suppl. ): 464A, 1998