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- PDB-9pns: Structure of human serotonin transporter bound to small molecule ... -

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Basic information

Entry
Database: PDB / ID: 9pns
TitleStructure of human serotonin transporter bound to small molecule zPZd in lipid nanodisc and NaCl
Components
  • 15B8 Fab heavy chain
  • 15B8 Fab light chain
  • Sodium-dependent serotonin transporter
KeywordsTRANSPORT PROTEIN/IMMUNE SYSTEM/INHIBITOR / Neurotransmitter Transporter / Inhibitor / Complex / TRANSPORT PROTEIN-IMMUNE SYSTEM-INHIBITOR complex
Function / homology
Function and homology information


negative regulation of cerebellar granule cell precursor proliferation / regulation of thalamus size / Serotonin clearance from the synaptic cleft / serotonergic synapse / positive regulation of serotonin secretion / negative regulation of synaptic transmission, dopaminergic / cocaine binding / serotonin:sodium:chloride symporter activity / cellular response to cGMP / enteric nervous system development ...negative regulation of cerebellar granule cell precursor proliferation / regulation of thalamus size / Serotonin clearance from the synaptic cleft / serotonergic synapse / positive regulation of serotonin secretion / negative regulation of synaptic transmission, dopaminergic / cocaine binding / serotonin:sodium:chloride symporter activity / cellular response to cGMP / enteric nervous system development / negative regulation of organ growth / sodium ion binding / serotonin uptake / neurotransmitter transmembrane transporter activity / vasoconstriction / monoamine transmembrane transporter activity / monoamine transport / serotonin binding / brain morphogenesis / syntaxin-1 binding / antiporter activity / negative regulation of neuron differentiation / male mating behavior / neurotransmitter transport / nitric-oxide synthase binding / amino acid transport / membrane depolarization / conditioned place preference / monoatomic cation channel activity / behavioral response to cocaine / cellular response to retinoic acid / positive regulation of cell cycle / endomembrane system / response to nutrient / sodium ion transmembrane transport / circadian rhythm / platelet aggregation / integrin binding / response to toxic substance / memory / actin filament binding / response to estradiol / presynaptic membrane / response to hypoxia / postsynaptic membrane / endosome membrane / neuron projection / membrane raft / response to xenobiotic stimulus / focal adhesion / synapse / positive regulation of gene expression / identical protein binding / plasma membrane
Similarity search - Function
Sodium:neurotransmitter symporter, serotonin, N-terminal / Serotonin (5-HT) neurotransmitter transporter, N-terminus / Sodium:neurotransmitter symporter family signature 2. / Sodium:neurotransmitter symporter family signature 1. / Sodium:neurotransmitter symporter / Sodium:neurotransmitter symporter superfamily / Sodium:neurotransmitter symporter family / Sodium:neurotransmitter symporter family profile.
Similarity search - Domain/homology
: / Sodium-dependent serotonin transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsBillesboelle, C.B. / Manglik, A.
Funding support United States, 1items
OrganizationGrant numberCountry
Defense Advanced Research Projects Agency (DARPA)HR0011-19-2-0020 United States
CitationJournal: J Med Chem / Year: 2026
Title: Large Library Docking for Polypharmacology.
Authors: Yujin Wu / Seth Vigneron / Joao Braz / Karthik Srinivasan / Elissa A Fink / Xi-Ping Huang / Xinyu Xu / Harald Huebner / Joseph Y Kim / Jing Wang / Tara Pfeiffer / Kensuke Sakamoto / Dmytro S ...Authors: Yujin Wu / Seth Vigneron / Joao Braz / Karthik Srinivasan / Elissa A Fink / Xi-Ping Huang / Xinyu Xu / Harald Huebner / Joseph Y Kim / Jing Wang / Tara Pfeiffer / Kensuke Sakamoto / Dmytro S Radchenko / Ramona M Rodriguiz / Yurii S Moroz / John J Irwin / Peter Gmeiner / Christian Billesboelle / Bryan L Roth / Allan I Basbaum / Aashish Manglik / William C Wetsel / Brian K Shoichet /
Abstract: Polypharmacological molecules are attractive for complex illnesses. Here, we explored large library docking for joint activity against target pairs. Retrospectively, as libraries grew, so too did the ...Polypharmacological molecules are attractive for complex illnesses. Here, we explored large library docking for joint activity against target pairs. Retrospectively, as libraries grew, so too did the number of likely dual-activity molecules. In prospective docking of a 900-million molecule library against three target pairs (α/SERT, MOR/SERT, and α/MOR), we sought analgesic compounds. Both the α/SERT and SERT/MOR campaigns led to dual binders with low μM to high nM activities with high hit rates; tetrahydropyridines from the α/SERT campaign were also active against 5-HT. However, even though cryo-EM structures confirmed the docking-predicted poses, optimization struggled to improve potency. Still, in mouse behavioral assays, the most potent α/SERT compound (') was effective against pain without inducing conditioned place preference, and the molecule had potent antidepression and anxiolytic drug-like behavior, consistent with its SERT/5-HT activities. This study reveals both advantages and challenges of docking for polypharmacology.
History
DepositionJul 21, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 4, 2026Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Sodium-dependent serotonin transporter
B: 15B8 Fab heavy chain
C: 15B8 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)86,3825
Polymers86,1343
Non-polymers2482
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Sodium-dependent serotonin transporter / SERT / 5HT transporter / 5HTT / Solute carrier family 6 member 4


Mass: 61062.129 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC6A4, HTT, SERT / Production host: Homo sapiens (human) / References: UniProt: P31645
#2: Antibody 15B8 Fab heavy chain


Mass: 13166.742 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#3: Antibody 15B8 Fab light chain


Mass: 11905.246 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-A1CIZ / (6M)-1-methyl-6-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole


Mass: 212.290 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H16N2 / Feature type: SUBJECT OF INVESTIGATION
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: Human serotonin transporter in complex with Fab15B8 bound to zPZd in NaCl
Type: COMPLEX / Entity ID: #1-#3 / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2100 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 47.7 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.5.3particle selection
4cryoSPARC4.5.3CTF correction
10cryoSPARC4.5.3initial Euler assignment
13cryoSPARC4.5.33D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 9815 / Symmetry type: POINT

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