ArticleProteins2009
Structural determinants of species-selective substrate recognition in human and Drosophila serotonin transporters revealed through computational docking studies.
Article in Proteins, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 56 citations in OpenAlex.
- Applications and Potential of In Silico Approaches for Psychedelic Chemistry.Molecules (Basel, Switzerland) · 2023Review
- Single amino acid residue mediates reciprocal specificity in two mosquito odorant receptors.eLife · 2022Article
- Structural Insights into the Substrate Transport Mechanisms in GTR Transporters through Ensemble Docking.International journal of molecular sciences · 2022Article
- Glycine Transporter 2: Mechanism and Allosteric Modulation.Frontiers in molecular biosciences · 2021Review
- Mechanism of Paroxetine (Paxil) Inhibition of the Serotonin Transporter.Scientific reports · 2016Article
- Article
- Computational and biochemical docking of the irreversible cocaine analog RTI 82 directly demonstrates ligand positioning in the dopamine transporter central substrate-binding site.The Journal of biological chemistry · 2014Article
- Conformational changes in dopamine transporter intracellular regions upon cocaine binding and dopamine translocation.Neurochemistry international · 2014Article
- Stereoselective inhibition of serotonin transporters by antimalarial compounds.Neurochemistry international · 2014Article
- Computational design of protein-small molecule interfaces.Journal of structural biology · 2014Article
- The two Na+ sites in the human serotonin transporter play distinct roles in the ion coupling and electrogenicity of transport.The Journal of biological chemistry · 2014Article
- Computational methods in drug discovery.Pharmacological reviews · 2014Review
- Article
- Synthesis, antidepressant evaluation and docking studies of long-chain alkylnitroquipazines as serotonin transporter inhibitors.Chemical biology & drug design · 2013Article
- Comparative modeling of the human monoamine transporters: similarities in substrate binding.ACS chemical neuroscience · 2013Article
- Mutational analysis of the high-affinity zinc binding site validates a refined human dopamine transporter homology model.PLoS computational biology · 2013Article
- Small-molecule ligand docking into comparative models with Rosetta.Nature protocols · 2013Article
- Interaction of antidepressants with the serotonin and norepinephrine transporters: mutational studies of the S1 substrate binding pocket.The Journal of biological chemistry · 2012Article
- Monoamine transporter structure, function, dynamics, and drug discovery: a computational perspective.The AAPS journal · 2012Review
- Bioinformatics and variability in drug response: a protein structural perspective.Journal of the Royal Society, Interface · 2012Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
To identify potential determinants of substrate selectivity in serotonin (5-HT) transporters (SERT), models of human and Drosophila serotonin transporters (hSERT, dSERT) were built based on the leucine transporter (LeuT(Aa)) structure reported by Yamashita et al. (Nature 2005;437:215-223), PBDID 2A65. Although the overall amino acid identity between SERTs and the LeuT(Aa) is only 17%, it increases to above 50% in the first shell of the putative 5-HT binding site, allowing de novo computational docking of tryptamine derivatives in atomic detail. Comparison of hSERT and dSERT complexed with substrates pinpoints likely structural determinants for substrate binding. Forgoing the use of experimental transport and binding data of tryptamine derivatives for construction of these models enables us to critically assess and validate their predictive power: A single 5-HT binding mode was identified that retains the amine placement observed in the LeuT(Aa) structure, matches site-directed mutagenesis and substituted cysteine accessibility method (SCAM) data, complies with support vector machine derived relations activity relations, and predicts computational binding energies for 5-HT analogs with a significant correlation coefficient (R = 0.72). This binding mode places 5-HT deep in the binding pocket of the SERT with the 5-position near residue hSERT A169/dSERT D164 in transmembrane helix 3, the indole nitrogen next to residue Y176/Y171, and the ethylamine tail under residues F335/F327 and S336/S328 within 4 A of residue D98. Our studies identify a number of potential contacts whose contribution to substrate binding and transport was previously unsuspected.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.