8uhb

Cryo-EM Structure of the Ro5256390-bound hTA1-Gs heterotrimer signaling complex

Structural highlights

8uhb is a 5 chain structure with sequence from Homo sapiens, Lama glama and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.35Å
Ligands:	WV8
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

C562_ECOLX Electron-transport protein of unknown function.ADRB2_HUMAN Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. The beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine.TAAR1_HUMAN Intracellular G-protein coupled receptor for trace amines, which recognizes endogenous amine-containing metabolites such as beta-phenylethylamine (beta-PEA), 3-iodothyronamine (T1AM), isoamylamine (IAA), cadaverine (CAD), cyclohexylamine (CHA), p-tyramine (p-TYR), trimethylamine (TMA), octopamine and tryptamine (PubMed:11459929, PubMed:11723224, PubMed:15718104, PubMed:31399635, PubMed:36100653, PubMed:37935376, PubMed:37935377, PubMed:37963465, PubMed:38168118). Also functions as a receptor for various drugs and psychoactive substances, such as amphetamine and methamphetamine (PubMed:31399635, PubMed:37935376, PubMed:37935377). Unresponsive to classical biogenic amines, such as epinephrine and histamine and only partially activated by dopamine and serotonin (PubMed:11459929, PubMed:11723224). Expressed in both the central and peripheral nervous system: TAAR1 activation regulates the activity of several neurotransmitter signaling pathways by (1) decreasing the basal firing rates of the neurons involved and by (2) lowering the sensitivity of receptors to neurotransmitters (PubMed:37935376, PubMed:37935377, PubMed:37963465, PubMed:38168118). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors (PubMed:31399635, PubMed:37935376, PubMed:37963465). TAAR1 is coupled with different G(i)/G(o)-, G(s)- or G(q)/G(11) classes of G alpha proteins depending on the ligand (PubMed:31399635, PubMed:37935376, PubMed:37963465). CAD-binding is coupled to G(i)/G(o) G alpha proteins and mediates inhibition of adenylate cyclase activity (PubMed:37935376, PubMed:37963465). T1AM- or beta-PEA-binding is coupled to G(s) G alpha proteins and mediates activation of adenylate cyclase activity (PubMed:37935376, PubMed:37963465). CHA- or IAA-binding is coupled to G(q)/G(11) G alpha proteins and activates phospholipase C-beta, releasing diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) second messengers (PubMed:37935376, PubMed:37963465). TMA-binding is coupled with all three G(i)/G(o)-, G(s)- or G(q)/G(11) G alpha protein subtypes (PubMed:37935376, PubMed:37963465). Amphetamine-binding is coupled with G(s)- or G(12)/G(13) G alpha protein subtypes (PubMed:31399635).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9]

Publication Abstract from PubMed

The human trace amine-associated receptor 1 (hTAAR1, hTA1) is a key regulator of monoaminergic neurotransmission and the actions of psychostimulants. Despite preclinical research demonstrating its tractability as a drug target, its molecular mechanisms of activation remain unclear. Moreover, poorly understood pharmacological differences between rodent and human TA1 complicate the translation of findings from preclinical disease models into novel pharmacotherapies. To elucidate hTA1's mechanisms on the molecular scale and investigate the underpinnings of its divergent pharmacology from rodent orthologs, we herein report the structure of the human TA1 receptor in complex with a Galphas heterotrimer. Our structure reveals shared structural elements with other TAARs, as well as with its closest monoaminergic orthologue, the serotonin receptor 5-HT4R. We further find that a single mutation dramatically shifts the selectivity of hTA1 towards that of its rodent orthologues, and report on the effects of substituting residues to those found in serotonin and dopamine receptors. Strikingly, we also discover that the atypical antipsychotic medication and pan-monoaminergic antagonist asenapine potently and efficaciously activates hTA1. Together our studies provide detailed insight into hTA1 structure and function, contrast its molecular pharmacology with that of related receptors, and uncover off-target activities of monoaminergic drugs at hTA1.

Molecular basis of human trace amine-associated receptor 1 activation.,Zilberg G, Parpounas AK, Warren AL, Yang S, Wacker D Nat Commun. 2024 Jan 2;15(1):108. doi: 10.1038/s41467-023-44601-4. PMID:38168118^[10]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, Durkin MM, Lakhlani PP, Bonini JA, Pathirana S, Boyle N, Pu X, Kouranova E, Lichtblau H, Ochoa FY, Branchek TA, Gerald C. Trace amines: identification of a family of mammalian G protein-coupled receptors. Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):8966-71. PMID:11459929 doi:10.1073/pnas.151105198
↑ Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, Darland T, Suchland KL, Pasumamula S, Kennedy JL, Olson SB, Magenis RE, Amara SG, Grandy DK. Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol. 2001 Dec;60(6):1181-8. PMID:11723224 doi:10.1124/mol.60.6.1181
↑ Lindemann L, Ebeling M, Kratochwil NA, Bunzow JR, Grandy DK, Hoener MC. Trace amine-associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors. Genomics. 2005 Mar;85(3):372-85. PMID:15718104 doi:10.1016/j.ygeno.2004.11.010
↑ Underhill SM, Hullihen PD, Chen J, Fenollar-Ferrer C, Rizzo MA, Ingram SL, Amara SG. Amphetamines signal through intracellular TAAR1 receptors coupled to Gα(13) and Gα(S) in discrete subcellular domains. Mol Psychiatry. 2021 Apr;26(4):1208-1223. PMID:31399635 doi:10.1038/s41380-019-0469-2
↑ Saarinen M, Mantas I, Flais I, Ågren R, Sahlholm K, Millan MJ, Svenningsson P. TAAR1 dependent and independent actions of the potential antipsychotic and dual TAAR1/5-HT(1A) receptor agonist SEP-383856. Neuropsychopharmacology. 2022 Dec;47(13):2319-2329. PMID:36100653 doi:10.1038/s41386-022-01421-2
↑ Xu Z, Guo L, Yu J, Shen S, Wu C, Zhang W, Zhao C, Deng Y, Tian X, Feng Y, Hou H, Su L, Wang H, Guo S, Wang H, Wang K, Chen P, Zhao J, Zhang X, Yong X, Cheng L, Liu L, Yang S, Yang F, Wang X, Yu X, Xu Y, Sun JP, Yan W, Shao Z. Ligand recognition and G protein coupling of trace amine receptor TAAR1. Nature. 2023 Nov 7. PMID:37935376 doi:10.1038/s41586-023-06804-z
↑ Liu H, Zheng Y, Wang Y, Wang Y, He X, Xu P, Huang S, Yuan Q, Zhang X, Wang L, Jiang K, Chen H, Li Z, Liu W, Wang S, Xu HE, Xu F. Recognition of methamphetamine and other amines by trace amine receptor TAAR1. Nature. 2023 Nov 7. PMID:37935377 doi:10.1038/s41586-023-06775-1
↑ Shang P, Rong N, Jiang JJ, Cheng J, Zhang MH, Kang D, Qi L, Guo L, Yang GM, Liu Q, Zhou Z, Li XB, Zhu KK, Meng QB, Han X, Yan W, Kong Y, Yang L, Wang X, Lei D, Feng X, Liu X, Yu X, Wang Y, Li Q, Shao ZH, Yang F, Sun JP. Structural and signaling mechanisms of TAAR1 enabled preferential agonist design. Cell. 2023 Nov 22;186(24):5347-5362.e24. PMID:37963465 doi:10.1016/j.cell.2023.10.014
↑ Zilberg G, Parpounas AK, Warren AL, Yang S, Wacker D. Molecular basis of human trace amine-associated receptor 1 activation. Nat Commun. 2024 Jan 2;15(1):108. PMID:38168118 doi:10.1038/s41467-023-44601-4
↑ Zilberg G, Parpounas AK, Warren AL, Yang S, Wacker D. Molecular basis of human trace amine-associated receptor 1 activation. Nat Commun. 2024 Jan 2;15(1):108. PMID:38168118 doi:10.1038/s41467-023-44601-4

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, Durkin MM, Lakhlani PP, Bonini JA, Pathirana S, Boyle N, Pu X, Kouranova E, Lichtblau H, Ochoa FY, Branchek TA, Gerald C. Trace amines: identification of a family of mammalian G protein-coupled receptors. Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):8966-71. PMID:11459929 doi:10.1073/pnas.151105198

[2] Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, Darland T, Suchland KL, Pasumamula S, Kennedy JL, Olson SB, Magenis RE, Amara SG, Grandy DK. Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol. 2001 Dec;60(6):1181-8. PMID:11723224 doi:10.1124/mol.60.6.1181

[3] Lindemann L, Ebeling M, Kratochwil NA, Bunzow JR, Grandy DK, Hoener MC. Trace amine-associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors. Genomics. 2005 Mar;85(3):372-85. PMID:15718104 doi:10.1016/j.ygeno.2004.11.010

[4] Underhill SM, Hullihen PD, Chen J, Fenollar-Ferrer C, Rizzo MA, Ingram SL, Amara SG. Amphetamines signal through intracellular TAAR1 receptors coupled to Gα(13) and Gα(S) in discrete subcellular domains. Mol Psychiatry. 2021 Apr;26(4):1208-1223. PMID:31399635 doi:10.1038/s41380-019-0469-2

[5] Saarinen M, Mantas I, Flais I, Ågren R, Sahlholm K, Millan MJ, Svenningsson P. TAAR1 dependent and independent actions of the potential antipsychotic and dual TAAR1/5-HT(1A) receptor agonist SEP-383856. Neuropsychopharmacology. 2022 Dec;47(13):2319-2329. PMID:36100653 doi:10.1038/s41386-022-01421-2

[6] Xu Z, Guo L, Yu J, Shen S, Wu C, Zhang W, Zhao C, Deng Y, Tian X, Feng Y, Hou H, Su L, Wang H, Guo S, Wang H, Wang K, Chen P, Zhao J, Zhang X, Yong X, Cheng L, Liu L, Yang S, Yang F, Wang X, Yu X, Xu Y, Sun JP, Yan W, Shao Z. Ligand recognition and G protein coupling of trace amine receptor TAAR1. Nature. 2023 Nov 7. PMID:37935376 doi:10.1038/s41586-023-06804-z

[7] Liu H, Zheng Y, Wang Y, Wang Y, He X, Xu P, Huang S, Yuan Q, Zhang X, Wang L, Jiang K, Chen H, Li Z, Liu W, Wang S, Xu HE, Xu F. Recognition of methamphetamine and other amines by trace amine receptor TAAR1. Nature. 2023 Nov 7. PMID:37935377 doi:10.1038/s41586-023-06775-1

[8] Shang P, Rong N, Jiang JJ, Cheng J, Zhang MH, Kang D, Qi L, Guo L, Yang GM, Liu Q, Zhou Z, Li XB, Zhu KK, Meng QB, Han X, Yan W, Kong Y, Yang L, Wang X, Lei D, Feng X, Liu X, Yu X, Wang Y, Li Q, Shao ZH, Yang F, Sun JP. Structural and signaling mechanisms of TAAR1 enabled preferential agonist design. Cell. 2023 Nov 22;186(24):5347-5362.e24. PMID:37963465 doi:10.1016/j.cell.2023.10.014

[9] Zilberg G, Parpounas AK, Warren AL, Yang S, Wacker D. Molecular basis of human trace amine-associated receptor 1 activation. Nat Commun. 2024 Jan 2;15(1):108. PMID:38168118 doi:10.1038/s41467-023-44601-4

[10] Zilberg G, Parpounas AK, Warren AL, Yang S, Wacker D. Molecular basis of human trace amine-associated receptor 1 activation. Nat Commun. 2024 Jan 2;15(1):108. PMID:38168118 doi:10.1038/s41467-023-44601-4

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

8uhb

Cryo-EM Structure of the Ro5256390-bound hTA1-Gs heterotrimer signaling complex

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools