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PDBsum entry 1mmh
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protein ligands Protein-protein interface(s) links
G protein-coupled receptor PDB id
1mmh

 

 

 

 

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Contents
Protein chains
32 a.a.
29 a.a.
26 a.a.
28 a.a.
30 a.a.
29 a.a.
34 a.a.
Ligands
NEC
Theoretical model
PDB id:
1mmh
Name: G protein-coupled receptor
Title: Molecular model of the human a2a adenosine receptor
Structure: Human a2a adenosine receptor. Chain: 1, 2, 3, 4, 5, 6, 7. Domain: seven transembrane helices only. Synonym: adoa2ar, p1 purinoceptor-a2a. Heterogen: n-ethyl-5'-carboxamidoadenosine (neca)
Source: Homo sapiens. Human. Tissue: brain
Authors: A.M.Van Rhee,J.Kim,J.Wess,T.Schoneberg,K.A.Jacobson
Key ref: J.Kim et al. (1995). Site-directed mutagenesis identifies residues involved in ligand recognition in the human A2a adenosine receptor. J Biol Chem, 270, 13987-13997. PubMed id: 7775460
Date:
27-Sep-95     Release date:   29-Jan-96    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P29274  (AA2AR_HUMAN) -  Adenosine receptor A2a from Homo sapiens
Seq:
Struc: 		412 a.a.
31 a.a.
Protein chain
Pfam   ArchSchema ?
P29274  (AA2AR_HUMAN) -  Adenosine receptor A2a from Homo sapiens
Seq:
Struc: 		412 a.a.
28 a.a.
Protein chain
Pfam   ArchSchema ?
P29274  (AA2AR_HUMAN) -  Adenosine receptor A2a from Homo sapiens
Seq:
Struc: 		412 a.a.
25 a.a.
Protein chain
Pfam   ArchSchema ?
P29274  (AA2AR_HUMAN) -  Adenosine receptor A2a from Homo sapiens
Seq:
Struc: 		412 a.a.
27 a.a.
Protein chain
Pfam   ArchSchema ?
P29274  (AA2AR_HUMAN) -  Adenosine receptor A2a from Homo sapiens
Seq:
Struc: 		412 a.a.
29 a.a.
Protein chain
Pfam   ArchSchema ?
P29274  (AA2AR_HUMAN) -  Adenosine receptor A2a from Homo sapiens
Seq:
Struc: 		412 a.a.
28 a.a.
Protein chain
Pfam   ArchSchema ?
P29274  (AA2AR_HUMAN) -  Adenosine receptor A2a from Homo sapiens
Seq:
Struc: 		412 a.a.
33 a.a.
Key:    PfamA domain  Secondary structure

 

 
J Biol Chem 270:13987-13997 (1995)
PubMed id: 7775460  
 
 
Site-directed mutagenesis identifies residues involved in ligand recognition in the human A2a adenosine receptor.
J.Kim, J.Wess, A.M.van Rhee, T.Schöneberg, K.A.Jacobson.
 
  ABSTRACT  
 
The A2a adenosine receptor is a member of the G-protein coupled receptor family, and its activation stimulates cyclic AMP production. To determine the residues which are involved in ligand binding, several residues in transmembrane domains 5-7 were individually replaced with alanine and other amino acids. The binding properties of the resultant mutant receptors were determined in transfected COS-7 cells. To study the expression levels in COS-7 cells, mutant receptors were tagged at their amino terminus with a hemagglutinin epitope, which allowed their immunological detection in the plasma membrane by the monoclonal antibody 12CA5. The functional properties of mutant receptors were determined by measuring stimulation of adenylate cyclase. Specific binding of [3H]CGS 21680 (15 nM) and [3H]XAC (4 nM), an A2a agonist and antagonist, respectively, was absent in the following Ala mutants: F182A, H250A, N253A, I274A, H278A, and S281A, although they were well expressed in the plasma membrane. The hydroxy group of Ser-277 is required for high affinity binding of agonists, but not antagonists. An N181S mutant lost affinity for adenosine agonists substituted at N6 or C-2, but not at C-5'. The mutant receptors I274A, S277A, and H278A showed full stimulation of adenylate cyclase at high concentrations of CGS 21680. The functional agonist potencies at mutant receptors that lacked radioligand binding were > 30-fold less than those at the wild type receptor. His-250 appears to be a required component of a hydrophobic pocket, and H-bonding to this residue is not essential. On the other hand, replacement of His-278 with other aromatic residues was not tolerated in ligand binding. Thus, some of the residues targeted in this study may be involved in the direct interaction with ligands in the human A2a adenosine receptor. A molecular model based on the structure of rhodopsin, in which the 5'-NH in NECA is hydrogen bonded to Ser-277 and His-278, was developed in order to visualize the environment of the ligand binding site.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21393508 F.Xu, H.Wu, V.Katritch, G.W.Han, K.A.Jacobson, Z.G.Gao, V.Cherezov, and R.C.Stevens (2011).
Structure of an agonist-bound human A2A adenosine receptor.
  Science, 332, 322-327.
PDB code: 3qak
20595055 H.Piirainen, Y.Ashok, R.T.Nanekar, and V.P.Jaakola (2011).
Structural features of adenosine receptors: from crystal to function.
  Biochim Biophys Acta, 1808, 1233-1244.  
20405927 J.Carlsson, L.Yoo, Z.G.Gao, J.J.Irwin, B.K.Shoichet, and K.A.Jacobson (2010).
Structure-based discovery of A2A adenosine receptor ligands.
  J Med Chem, 53, 3748-3755.  
19402631 A.A.Ivanov, D.Barak, and K.A.Jacobson (2009).
Evaluation of homology modeling of G-protein-coupled receptors in light of the A(2A) adenosine receptor crystallographic structure.
  J Med Chem, 52, 3284-3292.  
19757091 F.F.Sherbiny, A.C.Schiedel, A.Maass, and C.E.Müller (2009).
Homology modelling of the human adenosine A2B receptor based on X-ray structures of bovine rhodopsin, the beta2-adrenergic receptor and the human adenosine A2A receptor.
  J Comput Aided Mol Des, 23, 807-828.  
19405524 K.A.Jacobson (2009).
Functionalized congener approach to the design of ligands for G protein-coupled receptors (GPCRs).
  Bioconjug Chem, 20, 1816-1835.  
19558453 T.Suzuki, K.Namba, R.Yamagishi, H.Kaneko, T.Haga, and H.Nakata (2009).
A highly conserved tryptophan residue in the fourth transmembrane domain of the A adenosine receptor is essential for ligand binding but not receptor homodimerization.
  J Neurochem, 110, 1352-1362.  
17492754 A.Martinelli, and T.Tuccinardi (2008).
Molecular modeling of adenosine receptors: new results and trends.
  Med Res Rev, 28, 247-277.  
17668454 M.P.González, C.Terán, and M.Teijeira (2008).
Search for new antagonist ligands for adenosine receptors from QSAR point of view. How close are we?
  Med Res Rev, 28, 329-371.  
18442228 S.Costanzi (2008).
On the applicability of GPCR homology models to computer-aided drug discovery: a comparison between in silico and crystal structures of the beta2-adrenergic receptor.
  J Med Chem, 51, 2907-2914.  
18832607 V.P.Jaakola, M.T.Griffith, M.A.Hanson, V.Cherezov, E.Y.Chien, J.R.Lane, A.P.Ijzerman, and R.C.Stevens (2008).
The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist.
  Science, 322, 1211-1217.
PDB code: 3eml
17978889 Y.Ye, J.Wei, X.Dai, and Q.Gao (2008).
Computational studies of the binding modes of A 2A adenosine receptor antagonists.
  Amino Acids, 35, 389-396.  
17177231 G.Cristalli, B.Cacciari, D.Dal Ben, C.Lambertucci, S.Moro, G.Spalluto, and R.Volpini (2007).
Highlights on the Development of A(2A) Adenosine Receptor Agonists and Antagonists.
  ChemMedChem, 2, 260-281.  
17280720 K.A.Jacobson, Z.G.Gao, and B.T.Liang (2007).
Neoceptors: reengineering GPCRs to recognize tailored ligands.
  Trends Pharmacol Sci, 28, 111-116.  
16532452 K.Ye, E.W.Lameijer, M.W.Beukers, and A.P.Ijzerman (2006).
A two-entropies analysis to identify functional positions in the transmembrane region of class A G protein-coupled receptors.
  Proteins, 63, 1018-1030.  
16380972 S.Moro, Z.G.Gao, K.A.Jacobson, and G.Spalluto (2006).
Progress in the pursuit of therapeutic adenosine receptor antagonists.
  Med Res Rev, 26, 131-159.  
15034918 C.E.Spivak, and C.L.Beglan (2004).
Kinetics of beta-funaltrexamine binding to wild-type and mutant mu-opioid receptors expressed in Chinese hamster ovary cells.
  Synapse, 52, 123-135.  
14997566 H.Gutiérrez-de-Terán, N.B.Centeno, M.Pastor, and F.Sanz (2004).
Novel approaches for modeling of the A1 adenosine receptor and its agonist binding site.
  Proteins, 54, 705-715.  
15162487 P.R.Gouldson, N.J.Kidley, R.P.Bywater, G.Psaroudakis, H.D.Brooks, C.Diaz, D.Shire, and C.A.Reynolds (2004).
Toward the active conformations of rhodopsin and the beta2-adrenergic receptor.
  Proteins, 56, 67-84.  
11020228 C.E.Spivak, and C.L.Beglan (2000).
Kinetics of recovery from opioids at wild-type and mutant mu opioid receptors expressed in xenopus oocytes.
  Synapse, 38, 254-260.  
10722120 M.E.Olah, and G.L.Stiles (2000).
The role of receptor structure in determining adenosine receptor activity.
  Pharmacol Ther, 85, 55-75.  
10927024 Z.G.Gao, Q.Jiang, K.A.Jacobson, and A.P.Ijzerman (2000).
Site-directed mutagenesis studies of human A(2A) adenosine receptors: involvement of glu(13) and his(278) in ligand binding and sodium modulation.
  Biochem Pharmacol, 60, 661-668.  
9920286 B.Kull, G.Arslan, C.Nilsson, C.Owman, A.Lorenzen, U.Schwabe, and B.B.Fredholm (1999).
Differences in the order of potency for agonists but not antagonists at human and rat adenosine A2A receptors.
  Biochem Pharmacol, 57, 65-75.  
10797231 H.I.Mosberg (1999).
Complementarity of delta opioid ligand pharmacophore and receptor models.
  Biopolymers, 51, 426-439.  
10611496 J.L.Moreau, and G.Huber (1999).
Central adenosine A(2A) receptors: an overview.
  Brain Res Brain Res Rev, 31, 65-82.  
9174362 B.E.Cohen, G.Lee, K.A.Jacobson, Y.C.Kim, Z.Huang, E.J.Sorscher, and H.B.Pollard (1997).
8-cyclopentyl-1,3-dipropylxanthine and other xanthines differentially bind to the wild-type and delta F508 first nucleotide binding fold (NBF-1) domains of the cystic fibrosis transmembrane conductance regulator.
  Biochemistry, 36, 6455-6461.  
9129801 I.D.Pogozheva, A.L.Lomize, and H.I.Mosberg (1997).
The transmembrane 7-alpha-bundle of rhodopsin: distance geometry calculations with hydrogen bonding constraints.
  Biophys J, 72, 1963-1985.
PDB codes: 1boj 1bok
8884226 A.P.IJzerman, J.K.Von Frijtag Drabbe Künzel, J.Kim, Q.Jiang, and K.A.Jacobson (1996).
Site-directed mutagenesis of the human adenosine A2A receptor. Critical involvement of Glu13 in agonist recognition.
  Eur J Pharmacol, 310, 269-272.  
8979771 E.Ongini, and B.B.Fredholm (1996).
Pharmacology of adenosine A2A receptors.
  Trends Pharmacol Sci, 17, 364-372.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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