ジャーナル: Nat Commun / 年: 2024 タイトル: Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution. 著者: Manish K Yadav / Parishmita Sarma / Jagannath Maharana / Manisankar Ganguly / Sudha Mishra / Nashrah Zaidi / Annu Dalal / Vinay Singh / Sayantan Saha / Gargi Mahajan / Saloni Sharma / Mohamed ...著者: Manish K Yadav / Parishmita Sarma / Jagannath Maharana / Manisankar Ganguly / Sudha Mishra / Nashrah Zaidi / Annu Dalal / Vinay Singh / Sayantan Saha / Gargi Mahajan / Saloni Sharma / Mohamed Chami / Ramanuj Banerjee / Arun K Shukla / 要旨: The Hydroxycarboxylic acid receptor 2 (HCA2), also known as the niacin receptor or GPR109A, is a prototypical GPCR that plays a central role in the inhibition of lipolytic and atherogenic activities. ...The Hydroxycarboxylic acid receptor 2 (HCA2), also known as the niacin receptor or GPR109A, is a prototypical GPCR that plays a central role in the inhibition of lipolytic and atherogenic activities. Its activation also results in vasodilation that is linked to the side-effect of flushing associated with dyslipidemia drugs such as niacin. GPR109A continues to be a target for developing potential therapeutics in dyslipidemia with minimized flushing response. Here, we present cryo-EM structures of the GPR109A in complex with dyslipidemia drugs, niacin or acipimox, non-flushing agonists, MK6892 or GSK256073, and recently approved psoriasis drug, monomethyl fumarate (MMF). These structures elucidate the binding mechanism of agonists, molecular basis of receptor activation, and insights into biased signaling elicited by some of the agonists. The structural framework also allows us to engineer receptor mutants that exhibit G-protein signaling bias, and therefore, our study may help in structure-guided drug discovery efforts targeting this receptor.
全体 : Structure of GPR109A-G protein in complex with niacin
全体
名称: Structure of GPR109A-G protein in complex with niacin
要素
複合体: Structure of GPR109A-G protein in complex with niacin
複合体: Guanine nucleotide-binding protein G(o) subunit alpha
タンパク質・ペプチド: Guanine nucleotide-binding protein G(o) subunit alpha
複合体: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
タンパク質・ペプチド: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
複合体: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
タンパク質・ペプチド: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
複合体: ScFv16 Antibody fragment
タンパク質・ペプチド: ScFv16 (Antibody Fragment)
複合体: Hydroxycarboxylic acid receptor 2/GPR109A
タンパク質・ペプチド: Hydroxycarboxylic acid receptor 2
リガンド: NICOTINIC ACID
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超分子 #1: Structure of GPR109A-G protein in complex with niacin
超分子
名称: Structure of GPR109A-G protein in complex with niacin タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#5
由来(天然)
生物種: Homo sapiens (ヒト)
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超分子 #2: Guanine nucleotide-binding protein G(o) subunit alpha
超分子
名称: Guanine nucleotide-binding protein G(o) subunit alpha タイプ: complex / ID: 2 / 親要素: 1 / 含まれる分子: #1 詳細: This is a variant of Guanine nucleotide-binding protein G(o) subunit alpha called the "mini G(o) alpha"
由来(天然)
生物種: Homo sapiens (ヒト)
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超分子 #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1