Abstract:
:The aim of this study was to create and characterize constitutively active mutant (CAM) histamine H(1) receptors (H(1)R) using random mutagenesis methods to further investigate the activation process of the rhodopsin-like family of G protein-coupled receptors (GPCRs). This approach identified position 6.40 in TM 6 as a "hot spot" because mutation of Ile6.40(420) either to Glu, Gly, Ala, Arg, Lys, or Ser resulted in highly active CAM H(1)Rs, for which almost no histamine-induced receptor activation response could be detected. The highly conserved hydrophobic amino acid at position 6.40 defines, in a computational model of the H(1)R, the asparagine cage motif that restrains the side chain of Asn7.49 of the NPxxY motif toward transmembrane domain (TM 6) in the inactive state of the receptor. Mutation of the asparagine cage into Ala or Gly, removing the interfering bulky constraints, increases the constitutive activity of the receptor. The fact that the Ile6.40(420)Arg/Lys/Glu mutant receptors are highly active CAM H(1)Rs leads us to suggest that a positively charged residue, presumably the highly conserved Arg3.50 from the DRY motif, interacts in a direct or an indirect (through other side chains or/and internal water molecules) manner with the acidic Asp2.50..Asn7.49 pair for receptor activation.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Bakker RA,Jongejan A,Sansuk K,Hacksell U,Timmerman H,Brann MR,Weiner DM,Pardo L,Leurs Rdoi
10.1124/mol.107.038547subject
Has Abstractpub_date
2008-01-01 00:00:00pages
94-103issue
1eissn
0026-895Xissn
1521-0111pii
mol.107.038547journal_volume
73pub_type
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