Abstract:
:The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents including selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). Because eukaryotic BATs are recalcitrant to crystallographic analysis, our understanding of the mechanism of these inhibitors and antidepressants is limited. LeuT is a bacterial homologue of BATs and has proven to be a valuable paradigm for understanding relationships between their structure and function. However, because only approximately 25% of the amino acid sequence of LeuT is in common with that of BATs, and as LeuT is a promiscuous amino acid transporter, it does not recapitulate the pharmacological properties of BATs. Indeed, SSRIs and TCAs bind in the extracellular vestibule of LeuT and act as non-competitive inhibitors of transport. By contrast, multiple studies demonstrate that both TCAs and SSRIs are competitive inhibitors for eukaryotic BATs and bind to the primary binding pocket. Here we engineered LeuT to harbour human BAT-like pharmacology by mutating key residues around the primary binding pocket. The final LeuBAT mutant binds the SSRI sertraline with a binding constant of 18 nM and displays high-affinity binding to a range of SSRIs, SNRIs and a TCA. We determined 12 crystal structures of LeuBAT in complex with four classes of antidepressants. The chemically diverse inhibitors have a remarkably similar mode of binding in which they straddle transmembrane helix (TM) 3, wedge between TM3/TM8 and TM1/TM6, and lock the transporter in a sodium- and chloride-bound outward-facing open conformation. Together, these studies define common and simple principles for the action of SSRIs, SNRIs and TCAs on BATs.
journal_name
Naturejournal_title
Natureauthors
Wang H,Goehring A,Wang KH,Penmatsa A,Ressler R,Gouaux Edoi
10.1038/nature12648subject
Has Abstractpub_date
2013-11-07 00:00:00pages
141-5issue
7474eissn
0028-0836issn
1476-4687pii
nature12648journal_volume
503pub_type
杂志文章相关文献
NATURE文献大全abstract::Haemophilia B (Christmas disease) is an inherited, recessive, sex-linked, haemorrhagic condition caused by a defect in the intrinsic clotting factor IX. This disease occurs in males at a frequency of approximately 1 in 30,000. Patients differ in the severity of their clinical symptoms, and variation in the clotting ac...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/316643a0
更新日期:1985-08-15 00:00:00
abstract::Fast radio bursts (FRBs) are millisecond-duration radio transients1,2 of unknown origin. Two possible mechanisms that could generate extremely coherent emission from FRBs invoke neutron star magnetospheres3-5 or relativistic shocks far from the central energy source6-8. Detailed polarization observations may help us t...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-020-2827-2
更新日期:2020-10-01 00:00:00
abstract:: ...
journal_title:Nature
pub_type: 新闻
doi:10.1038/d41586-018-07324-x
更新日期:2018-11-01 00:00:00
abstract::Sea ice and dust flux increased greatly in the Southern Ocean during the last glacial period. Palaeorecords provide contradictory evidence about marine productivity in this region, but beyond one glacial cycle, data were sparse. Here we present continuous chemical proxy data spanning the last eight glacial cycles (740...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature04614
更新日期:2006-03-23 00:00:00
abstract::This corrects the article DOI: 10.1038/nature24277. ...
journal_title:Nature
pub_type: 杂志文章,已发布勘误
doi:10.1038/nature25160
更新日期:2018-01-25 00:00:00
abstract::Psoriasis is a chronic inflammatory skin disorder that affects approximately 2-3% of the population worldwide and has severe effects on patients' physical and psychological well-being. The discovery that psoriasis is an immune-mediated disease has led to more targeted, effective therapies; recent advances have focused...
journal_title:Nature
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1038/nature14175
更新日期:2015-05-14 00:00:00
abstract::The HLA-D region of the human major histocompatibility complex (MHC) has been shown to be homologous to the murine I region in terms of both structure and function. Both regions encode class II MHC molecules which restrict T-lymphocyte interactions with antigen-presenting cells. We have recently described the MHC rest...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/301716a0
更新日期:1983-02-24 00:00:00
abstract::Mutation of the XRCC4 gene in mammalian cells prevents the formation of the signal and coding joints in the V(D)J recombination reaction, which is necessary for production of a functional immunoglobulin gene, and renders the cells highly sensitive to ionizing radiation. However, XRCC4 shares no sequence homology with ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/41358
更新日期:1997-07-31 00:00:00
abstract::T cells recognize foreign proteins as peptides bound to self molecules encoded by the major histocompatibility complex (MHC). The kinetics of interaction between purified class II MHC molecules and peptides is unusual, in that the rate of association is very slow, but once formed, the complexes are extremely stable. T...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/342800a0
更新日期:1989-12-14 00:00:00
abstract::The evolutionary history of extant hominoids (humans and apes) remains poorly understood. The African fossil record during the crucial time period, the Miocene epoch, largely comprises isolated jaws and teeth, and little is known about ape cranial evolution. Here we report on the, to our knowledge, most complete fossi...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature23456
更新日期:2017-08-09 00:00:00
abstract::Magnetic compass information has a key role in bird orientation, but the physiological mechanisms enabling birds to sense the Earth's magnetic field remain one of the unresolved mysteries in biology. Two biophysical mechanisms have become established as the most promising magnetodetection candidates. The iron-mineral-...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature08528
更新日期:2009-10-29 00:00:00
abstract::The intestinal tract maintains proper function by replacing aged cells with freshly produced cells that arise from a population of self-renewing intestinal stem cells (ISCs). In the mammalian intestine, ISC self renewal, amplification and differentiation take place along the crypt-villus axis, and are controlled by th...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature07156
更新日期:2008-07-31 00:00:00
abstract::Glycine is an important inhibitory transmitter in the brainstem and spinal cord. In the trigeminal subnucleus caudalis (medullary dorsal horn) and in the spinal dorsal horn (the relaying centres for processing pain and sensory information), glycine inhibits the glutamate-evoked depolarization and depresses firing of n...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/348242a0
更新日期:1990-11-15 00:00:00
abstract::The generation of reprogrammed induced pluripotent stem cells (iPSCs) from patients with defined genetic disorders holds the promise of increased understanding of the aetiologies of complex diseases and may also facilitate the development of novel therapeutic interventions. We have generated iPSCs from patients with L...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature09005
更新日期:2010-06-10 00:00:00
abstract::The creation of neural circuits depends on the formation of synapses between specific sets of neurons. Little is known, however, of the molecular mechanisms governing synaptic choice. A mutation in the unc-4 gene alters the pattern of synaptic input to one class of motor neurons in the Caenorhabditis elegans ventral n...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/355841a0
更新日期:1992-02-27 00:00:00
abstract::The Tharsis region is the largest volcanic complex on Mars and in the Solar System. Young lava flows cover its surface (from the Amazonian period, less than 3 billion years ago) but its growth started during the Noachian era (more than 3.7 billion years ago). Its position has induced a reorientation of the planet with...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature17171
更新日期:2016-03-17 00:00:00
abstract::Most neurons of the mammalian central nervous system (CNS) lose the ability to regenerate severed axons in vivo after a certain point in development. At least part of this loss in regenerative potential is intrinsic to neurons. Although embryonic retinal ganglion cells (RGCs) can grow axons into tectum of any age, mos...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/385434a0
更新日期:1997-01-30 00:00:00
abstract::A balance between pro- and anti-inflammatory mechanisms at mucosal interfaces, which are sites of constitutive exposure to microbes and non-microbial foreign substances, allows for efficient protection against pathogens yet prevents adverse inflammatory responses associated with allergy, asthma and intestinal inflamma...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature10772
更新日期:2012-02-08 00:00:00
abstract::Fibres in the mammalian optic nerve are generally thought to be organised retinotopically. Recording electrophysiologically from the cat optic nerve, we found little evidence to support this notion, which led us to investigate the problem by anatomical methods. We made a localised injection of horseradish peroxidase i...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/282720a0
更新日期:1979-12-13 00:00:00
abstract::The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal ti...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-019-1672-7
更新日期:2019-10-01 00:00:00
abstract::P2Y receptors (P2YRs), a family of purinergic G-protein-coupled receptors (GPCRs), are activated by extracellular nucleotides. There are a total of eight distinct functional P2YRs expressed in human, which are subdivided into P2Y1-like receptors and P2Y12-like receptors. Their ligands are generally charged molecules w...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature13083
更新日期:2014-05-01 00:00:00
abstract::To ensure cell survival, it is essential that the ubiquitous pro-apoptotic machinery is kept quiescent. As death is irreversible, cells must continually integrate developmental information with regulatory inputs to control the switch between repressing and activating apoptosis. Inappropriate activation or suppression ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature01920
更新日期:2003-08-28 00:00:00
abstract::Globular star clusters are compact and massive stellar systems old enough to have witnessed the entire history of our Galaxy, the Milky Way. Although recent results suggest that their formation may have been more complex than previously thought, they still are the best approximation to a stellar population formed over...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature08581
更新日期:2009-11-26 00:00:00
abstract::During development, neuronal survival is regulated by the limited availability of neurotrophins, which are proteins of the nerve growth factor (NGF) family. Activation of specific trk tyrosine kinase receptors by the neurotrophins blocks programmed cell death. The trkA-specific ligand NGF has also been shown to activa...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/383166a0
更新日期:1996-09-12 00:00:00
abstract::Breast cancer patients with the same stage of disease can have markedly different treatment responses and overall outcome. The strongest predictors for metastases (for example, lymph node status and histological grade) fail to classify accurately breast tumours according to their clinical behaviour. Chemotherapy or ho...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/415530a
更新日期:2002-01-31 00:00:00
abstract::Established infections with the human and simian immunodeficiency viruses (HIV and SIV, respectively) are thought to be permanent with even the most effective immune responses and antiretroviral therapies only able to control, but not clear, these infections. Whether the residual virus that maintains these infections ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature12519
更新日期:2013-10-03 00:00:00
abstract::The antigen CD10 (common acute lymphoblastic leukaemia antigen), which is the zinc metalloprotease, neutral endopeptidase 24.11 (also known as NEP or 'enkephalinase'), is expressed by acute lymphoblastic leukaemias, normal lymphoid progenitors, mature polymorphonuclear leukocytes and certain nonhaematopoietic cells. C...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/347394a0
更新日期:1990-09-27 00:00:00
abstract::The spectral purity of an oscillator is central to many applications, such as detecting gravity waves, defining the second, ground-state cooling and quantum manipulation of nanomechanical objects, and quantum computation. Recent proposals suggest that laser oscillators which use very narrow optical transitions in atom...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature10920
更新日期:2012-04-04 00:00:00
abstract::Topological insulators-materials that are insulating in the bulk but allow electrons to flow on their surface-are striking examples of materials in which topological invariants are manifested in robustness against perturbations such as defects and disorder1. Their most prominent feature is the emergence of edge states...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-018-0601-5
更新日期:2018-10-01 00:00:00
abstract::Retinoid X receptor (RXR) plays a central role in the regulation of many intracellular receptor signalling pathways and can mediate ligand-dependent transcription, acting as a homodimer or as a heterodimer. Here we identify an antagonist towards RXR homodimers which also functions as an agonist when RXR is paired as a...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/383450a0
更新日期:1996-10-03 00:00:00