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- PDB-8fyl: Vilazodone-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex -

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Basic information

Entry
Database: PDB / ID: 8fyl
TitleVilazodone-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Soluble cytochrome b562,5-hydroxytryptamine receptor 1A,5-hydroxytryptamine receptor 1A
KeywordsSIGNALING PROTEIN / GPCR Signaling Complex / Serotonin Receptor
Function / homology
Function and homology information


regulation of serotonin secretion / adenylate cyclase-inhibiting serotonin receptor signaling pathway / regulation of hormone secretion / regulation of behavior / Serotonin receptors / receptor-receptor interaction / serotonin receptor signaling pathway / regulation of dopamine metabolic process / serotonin metabolic process / serotonin binding ...regulation of serotonin secretion / adenylate cyclase-inhibiting serotonin receptor signaling pathway / regulation of hormone secretion / regulation of behavior / Serotonin receptors / receptor-receptor interaction / serotonin receptor signaling pathway / regulation of dopamine metabolic process / serotonin metabolic process / serotonin binding / G protein-coupled serotonin receptor activity / gamma-aminobutyric acid signaling pathway / exploration behavior / neurotransmitter receptor activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / regulation of vasoconstriction / behavioral fear response / T cell migration / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Regulation of insulin secretion / G protein-coupled receptor binding / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / response to peptide hormone / G beta:gamma signalling through CDC42 / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / cellular response to prostaglandin E stimulus / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / cell cortex / midbody / fibroblast proliferation / G alpha (i) signalling events / G alpha (s) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / chemical synaptic transmission / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / GTPase activity / centrosome / dendrite / positive regulation of cell population proliferation / synapse / protein-containing complex binding / nucleolus / GTP binding / magnesium ion binding / signal transduction / extracellular exosome / nucleoplasm
Similarity search - Function
5-Hydroxytryptamine 1A receptor / 5-hydroxytryptamine receptor family / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit ...5-Hydroxytryptamine 1A receptor / 5-hydroxytryptamine receptor family / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-J40 / CHOLESTEROL HEMISUCCINATE / Chem-YG7 / 5-hydroxytryptamine receptor 1A / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.94 Å
AuthorsWarren, A.L. / Zilberg, G. / Capper, M.J. / Wacker, D.
Funding support United States, 5items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM 133504 United States
Other privateEdward Mallinckrodt, Jr. Foundation
Other privateAlfred P Sloan Foundationuroscience
Other privateMcKnight Foundation
Other privateIrma T. Hirschl/Monique Weill-Caulier Trust
CitationJournal: Nature / Year: 2024
Title: Structural pharmacology and therapeutic potential of 5-methoxytryptamines.
Authors: Audrey L Warren / David Lankri / Michael J Cunningham / Inis C Serrano / Lyonna F Parise / Andrew C Kruegel / Priscilla Duggan / Gregory Zilberg / Michael J Capper / Vaclav Havel / Scott J ...Authors: Audrey L Warren / David Lankri / Michael J Cunningham / Inis C Serrano / Lyonna F Parise / Andrew C Kruegel / Priscilla Duggan / Gregory Zilberg / Michael J Capper / Vaclav Havel / Scott J Russo / Dalibor Sames / Daniel Wacker /
Abstract: Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders. These compounds are thought to mediate their ...Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT (ref. ). However, 5-HT also plays a part in the behavioural effects of tryptamine hallucinogens, particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads. Although 5-HT is a validated therapeutic target, little is known about how psychedelics engage 5-HT and which effects are mediated by this receptor. Here we map the molecular underpinnings of 5-MeO-DMT pharmacology through five cryogenic electron microscopy (cryo-EM) structures of 5-HT, systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure-activity relationship analyses of 5-methoxytryptamines at both 5-HT and 5-HT enable the characterization of molecular determinants of 5-HT signalling potency, efficacy and selectivity. Moreover, we contrast the structural interactions and in vitro pharmacology of 5-MeO-DMT and analogues to the pan-serotonergic agonist LSD and clinically used 5-HT agonists. We show that a 5-HT-selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals. Our studies uncover molecular aspects of 5-HT-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.
History
DepositionJan 26, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 15, 2024Provider: repository / Type: Initial release
Revision 1.1May 22, 2024Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jun 19, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 23, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
R: Soluble cytochrome b562,5-hydroxytryptamine receptor 1A,5-hydroxytryptamine receptor 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)151,9868
Polymers149,7164
Non-polymers2,2704
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40415.031 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 39418.086 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 with N-terminal his-tag and 3C cleavage site and GSSG linker
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 8506.765 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Protein , 1 types, 1 molecules R

#4: Protein Soluble cytochrome b562,5-hydroxytryptamine receptor 1A,5-hydroxytryptamine receptor 1A / 5-HT-1A / 5-HT1A / G-21 / Serotonin receptor 1A


Mass: 61375.930 Da / Num. of mol.: 1 / Mutation: 3
Source method: isolated from a genetically manipulated source
Details: N-terminal HA signal sequence, flag-tag, his-tag, tev cleavage site followed by soluble cytochrome b562 (E. coli) and truncated 5-hydroxytryptamine receptor 1A (Homo sapiens) with a point ...Details: N-terminal HA signal sequence, flag-tag, his-tag, tev cleavage site followed by soluble cytochrome b562 (E. coli) and truncated 5-hydroxytryptamine receptor 1A (Homo sapiens) with a point mutation at position 255 in the provided sequence. This mutation is in Ballesteros-Weinstein position 3.41 of 5-HT1A where the original leucine was mutated to a tryptophan. Cytochrome b562 (cybC, UniProt P0ABE7) is both n and c-terminally truncated with two point mutations.,N-terminal HA signal sequence, flag-tag, his-tag, tev cleavage site followed by soluble cytochrome b562 (E. coli) and truncated 5-hydroxytryptamine receptor 1A (Homo sapiens) with a point mutation at position 255 in the provided sequence. This mutation is in Ballesteros-Weinstein position 3.41 of 5-HT1A where the original leucine was mutated to a tryptophan. Cytochrome b562 (cybC, UniProt P0ABE7) is both n and c-terminally truncated with two point mutations.
Source: (gene. exp.) Homo sapiens (human) / Gene: cybC, HTR1A, ADRB2RL1, ADRBRL1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P08908

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Non-polymers , 3 types, 4 molecules

#5: Chemical ChemComp-J40 / [(2R)-1-[oxidanyl-[(2R,3R,5S,6R)-2,3,5,6-tetrakis(oxidanyl)-4-phosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-3-tetradecanoyloxy-propan-2-yl] (5E,8E)-hexadeca-5,8,11,14-tetraenoate


Mass: 854.895 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C39H68O16P2
#6: Chemical ChemComp-YG7 / 5-{4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl}-1-benzofuran-2-carboxamide


Mass: 441.525 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H27N5O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
#7: Chemical ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H50O4

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Serotonin 1A (5-HT1A) receptor-Gi1 protein complex / Type: COMPLEX
Details: Serotonin 1A (5-HT1A) receptor-Gi1 protein complex with components purified separately and assembled in vitro.
Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Escherichia coli, Homo sapiens
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm) / Plasmid: pFB
Buffer solutionpH: 7.4
Buffer component
IDConc.NameBuffer-ID
120 mMHEPES1
2100 mMsodium chloride1
30.001 % (w/v)LMNG1
40.0001 % (w/v)CHS1
50.0001 % (w/v)GDN1
SpecimenConc.: 18 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Sample was mono disperse following gel filtration. The sample was immediately concentrated for CryoEM grid preparation.
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE
Details: Blot force 3 for 3-5 seconds was used and subsequent grids were screened for ice thickness prior to data collection.

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 54.3 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2Leginonimage acquisition
4cryoSPARCCTF correction
7UCSF Chimeramodel fitting
9PHENIXmodel refinement
10Cootmodel refinement
11REFMACmodel refinement
13cryoSPARCfinal Euler assignment
14cryoSPARCclassification
15cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 18088270
3D reconstructionResolution: 2.94 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 785536
Details: Final reconstruction generated with NU Refinement in cryoSPARC.
Num. of class averages: 1 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0037469
ELECTRON MICROSCOPYf_angle_d0.46910118
ELECTRON MICROSCOPYf_dihedral_angle_d6.7371108
ELECTRON MICROSCOPYf_chiral_restr0.0411162
ELECTRON MICROSCOPYf_plane_restr0.0031288

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