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Neuropharmacology. 2018 Nov 1. pii: S0028-3908(18)30824-4. doi: 10.1016/j.neuropharm.2018.10.040. [Epub ahead of print]

Computation-guided analysis of paroxetine binding to hSERT reveals functionally important structural elements and dynamics.

Author information

1
Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD, 21224, United States.
2
Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, United States.
3
Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD, 21224, United States. Electronic address: anewman@intra.nida.nih.gov.
4
Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, United States. Electronic address: satinder.k.singh@yale.edu.
5
Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD, 21224, United States. Electronic address: lei.shi2@nih.gov.

Abstract

The serotonin transporter (SERT) is one of the primary targets for medications to treat neuropsychiatric disorders and functions by exploiting pre-existing ion gradients of Na+, Cl-, and K+ to translocate serotonin from the synaptic cleft into the presynaptic neuron. Although recent hSERT crystal structures represent a milestone for structure-function analyses of mammalian neurotransmitter:sodium symporters, they are all derived from thermostabilized but transport-deficient constructs. Two of these structures are in complex with paroxetine, the most potent selective serotonin reuptake inhibitor known. In this study, by carrying out and analyzing the results of extensive and comparative molecular dynamics simulations while also re-evaluating the transport and binding properties of the thermostabilized constructs, we identified functionally important structural elements that are perturbed by these mutations, revealed unexpected dynamics in the central primary binding site of SERT, and uncovered a conceivable ambiguity in paroxetine's binding orientation. We propose that the favored entropy contribution plays a significant role in paroxetine's extraordinarily high affinity for SERT. Our findings lay the foundation for future mechanistic studies and rational design of high-affinity SERT inhibitors.

KEYWORDS:

Conformational thermostabilization; Molecular dynamics simulations; Paroxetine; Selective serotonin reuptake inhibitors; Serotonin transporter; X-ray crystallography

PMID:
30391505
PMCID:
PMC6494725
[Available on 2020-05-01]
DOI:
10.1016/j.neuropharm.2018.10.040

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