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PMID: 21885291 Published · ppublish English Journal Article

Structure of the adenosine A(2A) receptor in complex with ZM241385 and the xanthines XAC and caffeine.

Structure (London, England : 1993) ·Vol. 19 ·No. 9 ·2011-09-07 ·Pages 1283-93

Doré AS, Robertson N, Errey JC, Ng I, Hollenstein K, Tehan B, Hurrell E, Bennett K, Congreve M, Magnani F, Tate CG, Weir M, Marshall FH

Abstract

Methylxanthines, including caffeine and theophylline, are among the most widely consumed stimulant drugs in the world. These effects are mediated primarily via blockade of adenosine receptors. Xanthine analogs with improved properties have been developed as potential treatments for diseases such as Parkinson's disease. Here we report the structures of a thermostabilized adenosine A(2A) receptor in complex with the xanthines xanthine amine congener and caffeine, as well as the A(2A) selective inverse agonist ZM241385. The receptor is crystallized in the inactive state conformation as defined by the presence of a salt bridge known as the ionic lock. The complete third intracellular loop, responsible for G protein coupling, is visible consisting of extended helices 5 and 6. The structures provide new insight into the features that define the ligand binding pocket of the adenosine receptor for ligands of diverse chemotypes as well as the cytoplasmic regions that interact with signal transduction proteins.

MeSH Terms
Adenosine A2 Receptor Agonists/chemistry,pharmacology Amino Acid Motifs Amino Acid Sequence Amino Acid Substitution Binding Sites Caffeine/chemistry,pharmacology Crystallography, X-Ray HEK293 Cells Humans Hydrogen Bonding Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed Protein Binding Protein Stability Protein Structure, Tertiary Receptor, Adenosine A2A/chemistry,genetics,metabolism Surface Properties Triazines/chemistry,pharmacology Triazoles/chemistry,pharmacology Xanthines/chemistry,pharmacology
Chemicals
Adenosine A2 Receptor Agonists Receptor, Adenosine A2A Triazines Triazoles Xanthines ZM 241385 Caffeine 8-(4-((2-aminoethyl)aminocarbonylmethyloxy)phenyl)-1,3-dipropylxanthine
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Doré Andrew S
Heptares Therapeutics Ltd, BioPark, Welwyn Garden City, Herts, AL7 3AX, UK.
Robertson Nathan
Errey James C
Ng Irene
Hollenstein Kaspar
Tehan Ben
Hurrell Edward
Bennett Kirstie
Congreve Miles
Magnani Francesca
Tate Christopher G
Weir Malcolm
Marshall Fiona H
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Article Info
Journal
Structure (London, England : 1993)
Abbr.
Structure
ISSN
1878-4186
DOI
10.1016/j.str.2011.06.014
Published
2011-09-07
Pages
1283-93
Language
English
Region
United States
NLM ID
101087697
PMCID
PMC3732996
Subset
IM
Grants
Medical Research Council · MC_U105197215 · United Kingdom
Databases
PDB
3PWH, 3REY, 3RFM
Corrections
CommentIn
PMID: 21893281
External Links
PubMed source DOI: 10.1016/j.str.2011.06.014 PMC Full Text View journal details
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