General Information of Target

Target ID LDTP03605
Target Name Sodium-dependent serotonin transporter (SLC6A4)
Gene Name SLC6A4
Gene ID 6532
Synonyms
HTT; SERT; Sodium-dependent serotonin transporter; SERT; 5HT transporter; 5HTT; Solute carrier family 6 member 4
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Sequence
METTPLNSQKQLSACEDGEDCQENGVLQKVVPTPGDKVESGQISNGYSAVPSPGAGDDTR
HSIPATTTTLVAELHQGERETWGKKVDFLLSVIGYAVDLGNVWRFPYICYQNGGGAFLLP
YTIMAIFGGIPLFYMELALGQYHRNGCISIWRKICPIFKGIGYAICIIAFYIASYYNTIM
AWALYYLISSFTDQLPWTSCKNSWNTGNCTNYFSEDNITWTLHSTSPAEEFYTRHVLQIH
RSKGLQDLGGISWQLALCIMLIFTVIYFSIWKGVKTSGKVVWVTATFPYIILSVLLVRGA
TLPGAWRGVLFYLKPNWQKLLETGVWIDAAAQIFFSLGPGFGVLLAFASYNKFNNNCYQD
ALVTSVVNCMTSFVSGFVIFTVLGYMAEMRNEDVSEVAKDAGPSLLFITYAEAIANMPAS
TFFAIIFFLMLITLGLDSTFAGLEGVITAVLDEFPHVWAKRRERFVLAVVITCFFGSLVT
LTFGGAYVVKLLEEYATGPAVLTVALIEAVAVSWFYGITQFCRDVKEMLGFSPGWFWRIC
WVAISPLFLLFIICSFLMSPPQLRLFQYNYPYWSIILGYCIGTSSFICIPTYIAYRLIIT
PGTFKERIIKSITPETPTEIPCGDIRLNAV
Target Type
Successful
Target Bioclass
Transporter and channel
Family
Sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family, SLC6A4 subfamily
Subcellular location
Cell membrane
Function
Serotonin transporter that cotransports serotonin with one Na(+) ion in exchange for one K(+) ion and possibly one proton in an overall electroneutral transport cycle. Transports serotonin across the plasma membrane from the extracellular compartment to the cytosol thus limiting serotonin intercellular signaling . Essential for serotonin homeostasis in the central nervous system. In the developing somatosensory cortex, acts in glutamatergic neurons to control serotonin uptake and its trophic functions accounting for proper spatial organization of cortical neurons and elaboration of sensory circuits. In the mature cortex, acts primarily in brainstem raphe neurons to mediate serotonin uptake from the synaptic cleft back into the pre-synaptic terminal thus terminating serotonin signaling at the synapse. Modulates mucosal serotonin levels in the gastrointestinal tract through uptake and clearance of serotonin in enterocytes. Required for enteric neurogenesis and gastrointestinal reflexes. Regulates blood serotonin levels by ensuring rapid high affinity uptake of serotonin from plasma to platelets, where it is further stored in dense granules via vesicular monoamine transporters and then released upon stimulation. Mechanistically, the transport cycle starts with an outward-open conformation having Na1(+) and Cl(-) sites occupied. The binding of a second extracellular Na2(+) ion and serotonin substrate leads to structural changes to outward-occluded to inward-occluded to inward-open, where the Na2(+) ion and serotonin are released into the cytosol. Binding of intracellular K(+) ion induces conformational transitions to inward-occluded to outward-open and completes the cycle by releasing K(+) possibly together with a proton bound to Asp-98 into the extracellular compartment. Na1(+) and Cl(-) ions remain bound throughout the transport cycle . Additionally, displays serotonin-induced channel-like conductance for monovalent cations, mainly Na(+) ions. The channel activity is uncoupled from the transport cycle and may contribute to the membrane resting potential or excitability.
TTD ID
T27812
Uniprot ID
P31645
DrugMap ID
TT3ROYC
Ensemble ID
ENST00000261707.7
HGNC ID
HGNC:11050
ChEMBL ID
CHEMBL228

Target Site Mutations in Different Cell Lines

Cell line Mutation details Probe for labeling this protein in this cell
HT115 SNV: p.A401T DBIA    Probe Info 
KMS11 SNV: p.S532R DBIA    Probe Info 
MCC13 SNV: p.L292F DBIA    Probe Info 
NCIH446 SNV: p.G342R .
NCIH661 SNV: p.G517V .
OVCAR4 SNV: p.S48L DBIA    Probe Info 
SHP77 SNV: p.V281M DBIA    Probe Info 

Probe(s) Labeling This Target

ABPP Probe
Click To Hide/Show 2 Probe Related to This Target
Probe name Structure Binding Site(Ratio) Interaction ID Ref
DBIA
 Probe Info 
C2971(3.49); C636(2.36)  LDD3311  [1]
NAIA_5
 Probe Info 
C664(0.00); C1524(0.00); C431(0.00); C278(0.00)  LDD2224  [2]

Competitor(s) Related to This Target

Competitor ID Name Cell line Binding Site(Ratio) Interaction ID Ref
 LDCM0022  KB02 22RV1 C2971(7.55); C1998(3.29); C636(2.08)  LDD2243  [1]
 LDCM0023  KB03 22RV1 C2971(4.18); C1998(6.69); C636(2.15)  LDD2660  [1]
 LDCM0024  KB05 G361 C2971(3.49); C636(2.36)  LDD3311  [1]

References

1 DrugMap: A quantitative pan-cancer analysis of cysteine ligandability. Cell. 2024 May 9;187(10):2536-2556.e30. doi: 10.1016/j.cell.2024.03.027. Epub 2024 Apr 22.
Mass spectrometry data entry: PXD047840
2 N-Acryloylindole-alkyne (NAIA) enables imaging and profiling new ligandable cysteines and oxidized thiols by chemoproteomics. Nat Commun. 2023 Jun 15;14(1):3564. doi: 10.1038/s41467-023-39268-w.
Mass spectrometry data entry: PXD041264