Abstract:
:The transporters for the neurotransmitters serotonin and dopamine (SERT and DAT, respectively) are targets for drugs used in the treatment of mental disorders and widely used drugs of abuse. Studies of prokaryotic homologues have advanced our structural understanding of SERT and DAT, but it still remains enigmatic whether the human transporters contain one or two high-affinity substrate binding sites. We have designed and employed 24 bivalent ligands possessing a highly systematic combination of substrate moieties (serotonin and/or dopamine) and aliphatic or poly(ethylene glycol) spacers to reveal insight into substrate recognition in SERT and DAT. An optimized bivalent ligand comprising two serotonin moieties binds SERT with 3,800-fold increased affinity compared to that of serotonin, suggesting that the human transporters have two distinct substrate binding sites. We show that the bivalent ligands are inhibitors of SERT and an experimentally validated docking model suggests that the bivalent compounds bind with one substrate moiety in the central binding site (the S1 site), whereas the other substrate moiety binds in a distinct binding site (the S2 site). A systematic study of nonconserved SERT/DAT residues surrounding the proposed binding region showed that nonconserved binding site residues do not contribute to selective recognition of substrates in SERT or DAT. This study provides novel insight into the molecular basis for substrate recognition in human transporters and provides an improved foundation for the development of new drugs targeting SERT and DAT.
journal_name
ACS Chem Neuroscijournal_title
ACS chemical neuroscienceauthors
Andersen J,Ladefoged LK,Kristensen TN,Munro L,Grouleff J,Stuhr-Hansen N,Kristensen AS,Schiøtt B,Strømgaard Kdoi
10.1021/acschemneuro.6b00164subject
Has Abstractpub_date
2016-10-19 00:00:00pages
1406-1417issue
10issn
1948-7193journal_volume
7pub_type
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