2qb4

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{{STRUCTURE_2qb4| PDB=2qb4 | SCENE= }}
{{STRUCTURE_2qb4| PDB=2qb4 | SCENE= }}
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'''Crystal Structure Analysis of LeuT complexed with L-leucine, sodium and desipramine'''
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===Crystal Structure Analysis of LeuT complexed with L-leucine, sodium and desipramine===
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==Overview==
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Sodium-coupled transporters are ubiquitous pumps that harness pre-existing sodium gradients to catalyse the thermodynamically unfavourable uptake of essential nutrients, neurotransmitters and inorganic ions across the lipid bilayer. Dysfunction of these integral membrane proteins has been implicated in glucose/galactose malabsorption, congenital hypothyroidism, Bartter's syndrome, epilepsy, depression, autism and obsessive-compulsive disorder. Sodium-coupled transporters are blocked by a number of therapeutically important compounds, including diuretics, anticonvulsants and antidepressants, many of which have also become indispensable tools in biochemical experiments designed to probe antagonist binding sites and to elucidate transport mechanisms. Steady-state kinetic data have revealed that both competitive and noncompetitive modes of inhibition exist. Antagonist dissociation experiments on the serotonin transporter (SERT) have also unveiled the existence of a low-affinity allosteric site that slows the dissociation of inhibitors from a separate high-affinity site. Despite these strides, atomic-level insights into inhibitor action have remained elusive. Here we screen a panel of molecules for their ability to inhibit LeuT, a prokaryotic homologue of mammalian neurotransmitter sodium symporters, and show that the tricyclic antidepressant (TCA) clomipramine noncompetitively inhibits substrate uptake. Cocrystal structures show that clomipramine, along with two other TCAs, binds in an extracellular-facing vestibule about 11 A above the substrate and two sodium ions, apparently stabilizing the extracellular gate in a closed conformation. Off-rate assays establish that clomipramine reduces the rate at which leucine dissociates from LeuT and reinforce our contention that this TCA inhibits LeuT by slowing substrate release. Our results represent a molecular view into noncompetitive inhibition of a sodium-coupled transporter and define principles for the rational design of new inhibitors.
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The line below this paragraph, {{ABSTRACT_PUBMED_17687333}}, adds the Publication Abstract to the page
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(as it appears on PubMed at http://www.pubmed.gov), where 17687333 is the PubMed ID number.
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{{ABSTRACT_PUBMED_17687333}}
==About this Structure==
==About this Structure==
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==Reference==
==Reference==
Antidepressant binding site in a bacterial homologue of neurotransmitter transporters., Singh SK, Yamashita A, Gouaux E, Nature. 2007 Aug 23;448(7156):952-6. Epub 2007 Aug 8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17687333 17687333]
Antidepressant binding site in a bacterial homologue of neurotransmitter transporters., Singh SK, Yamashita A, Gouaux E, Nature. 2007 Aug 23;448(7156):952-6. Epub 2007 Aug 8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17687333 17687333]
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Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters., Yamashita A, Singh SK, Kawate T, Jin Y, Gouaux E, Nature. 2005 Sep 8;437(7056):215-23. Epub 2005 Jul 24. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16041361 16041361]
[[Category: Aquifex aeolicus]]
[[Category: Aquifex aeolicus]]
[[Category: Single protein]]
[[Category: Single protein]]
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[[Category: Transport]]
[[Category: Transport]]
[[Category: Transport protein]]
[[Category: Transport protein]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 14:39:18 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 08:20:32 2008''

Revision as of 05:20, 29 July 2008

Image:2qb4.png

Template:STRUCTURE 2qb4

Crystal Structure Analysis of LeuT complexed with L-leucine, sodium and desipramine

Template:ABSTRACT PUBMED 17687333

About this Structure

2QB4 is a Single protein structure of sequence from Aquifex aeolicus. Full crystallographic information is available from OCA.

Reference

Antidepressant binding site in a bacterial homologue of neurotransmitter transporters., Singh SK, Yamashita A, Gouaux E, Nature. 2007 Aug 23;448(7156):952-6. Epub 2007 Aug 8. PMID:17687333

Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters., Yamashita A, Singh SK, Kawate T, Jin Y, Gouaux E, Nature. 2005 Sep 8;437(7056):215-23. Epub 2005 Jul 24. PMID:16041361

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