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PMID: 12237474 Published · ppublish English Journal Article

Cannabinoid receptor-G protein interactions: G(alphai1)-bound structures of IC3 and a mutant with altered G protein specificity.

Protein science : a publication of the Protein Society ·Vol. 11 ·No. 10 ·2002-10-00 ·Pages 2526-31

Ulfers AL, McMurry JL, Miller A, Wang L, Kendall DA, Mierke DF

Abstract

The structure of the C-terminal region of the third cytoplasmic loop (IC3) of the cannabinoid receptor one (CB1) bound to G(alphai1) has been determined using transferred nuclear Overhauser effects (NOEs). The wild-type IC3 sequence is helical when associated with G(alphai1). In contrast, a peptide containing the amino-acid inversion, Ala(341)-Leu(342) adopts a single turn. These findings correlate with the attenuated G(i) association of CB1 with the Ala(341)-Leu(342) mutation previously observed in vivo and the diminished stimulation of G(alphai1) GTPase activity by the corresponding peptide demonstrated in vitro here. These results, the first to report the structure of a GPCR domain while associated with G protein, imply the C-terminus of CB1 IC3, a region with high-sequence conservation among G-protein coupled receptors, must be helical for efficient coupling and activation of the G(i) protein.

MeSH Terms
GTP-Binding Proteins/metabolism Mutation Protein Binding/genetics Protein Structure, Tertiary Receptors, Cannabinoid Receptors, Drug/genetics,metabolism Structure-Activity Relationship
Chemicals
Receptors, Cannabinoid Receptors, Drug GTP-Binding Proteins
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Ulfers Amy L
Department of Molecular Pharmacology, Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912, USA.
McMurry Jonathan L
Miller Alexander
Wang Ligong
Kendall Debra A
Mierke Dale F
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Article Info
Journal
Protein science : a publication of the Protein Society
Abbr.
Protein Sci
ISSN
0961-8368
DOI
10.1110/ps.0218402
Published
2002-10-00
Pages
2526-31
Language
English
Region
United States
NLM ID
9211750
PMCID
PMC2373710
Subset
IM
External Links
PubMed source DOI: 10.1110/ps.0218402 PMC Full Text View journal details
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