Linked Life Data

20404073

Source:http://linkedlifedata.com/resource/pubmed/id/20404073

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2010-6-21
pubmed:abstractText
The orexins and their receptors are involved in the regulation of arousal and sleep-wake cycle. Clinical investigation with almorexant has indicated that this dual OX antagonist is efficacious in inducing and maintaining sleep. Using site-directed mutagenesis, beta(2)-adrenergic-based OX(1) and OX(2) modeling, we have determined important molecular determinants of the ligand-binding pocket of OX(1) and OX(2). The conserved residues Asp(45.51), Trp(45.54), Tyr(5.38), Phe(5.42), Tyr(5.47), Tyr(6.48), and His(7.39) were found to be contributing to both orexin-A-binding sites at OX(1) and OX(2). Among these critical residues, five (positions 45.51, 45.54, 5.38, 5.42, and 7.39) were located on the C-terminal strand of the second extracellular loop (ECL2b) and in the top of TM domains at the interface to the main binding crevice, thereby suggesting superficial OX receptor interactions of orexin-A. We found that the mutations W214A(45.54), Y223A(5.38), F227A(5.42), Y317A(6.48), and H350A(7.39) resulted in the complete loss of both [(3)H]almorexant and [(3)H]N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA) binding affinities and also blocked their inhibition of orexin-A-evoked [Ca(2+)](i) response at OX(2). The crucial residues Gln126(3.32), Ala127(3.33), Trp206(45.54), Tyr215(5.38), Phe219(5.42), and His344(7.39) are shared between almorexant and 1-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-1-((S)-2-(5-phenyl-(1,3,4)oxadiazol-2-ylmethyl)-pyrrolidin-1-yl)-methanone (SB-674042) binding sites in OX(1). The nonconserved residue at position 3.33 of orexin receptors was identified as occupying a critical position that must be involved in subtype selectivity and also in differentiating two different antagonists for the same receptor. In summary, despite high similarities in the ligand-binding pockets of OX(1) and OX(2) and numerous aromatic/hydrophobic interactions, the local conformation of helix positions 3.32, 3.33, and 3.36 in transmembrane domain 3 and 45.51 in ECL2b provide the structural basis for pharmacologic selectivity between OX(1) and OX(2).
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
1521-0111
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
78
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
81-93
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Mapping the binding pocket of dual antagonist almorexant to human orexin 1 and orexin 2 receptors: comparison with the selective OX1 antagonist SB-674042 and the selective OX2 antagonist N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA).
pubmed:affiliation
F. Hoffmann-La Roche Ltd., Bldg. 69/333, CH-4070 Basel, Switzerland. parichehr.malherbe@roche.com
pubmed:publicationType
Journal Article, Comparative Study