PDBsum entry: 2qju

Transport protein

PDB id: 2qju

Contents

Protein chain

509 a.a. *

Ligands

BOG ×4

LEU

DSM

Metals

_NA ×2

_CL

Waters ×15

* Residue conservation analysis

PDB id:

2qju

Name:

Transport protein

Title:

Crystal structure of an nss homolog with bound antidepressan

Structure:

Transporter. Chain: a. Engineered: yes

Source:

Aquifex aeolicus. Organism_taxid: 224324. Strain: vf5. Gene: snf. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.90Å R-factor: 0.199 R-free: 0.220

Authors:

Z.Zhou,N.K.Karpowich,D.N.Wang,New York Consortium On Membran Structure (Nycomps)

Key ref:

Z.Zhou et al. (2007). LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake. Science, 317, 1390-1393. PubMed id: 17690258 DOI: 10.1126/science.1147614

Date:

09-Jul-07 Release date: 21-Aug-07

Protein chain

O67854  (O67854_AQUAE) -  Transporter

Seq: 513 a.a.

Struc: 509 a.a.

 Gene Ontology (GO) functional annotation 

• Cellular component: integral to membrane (1 term)
• Biological process: transport (2 terms)
• Biochemical function: symporter activity (2 terms)

DOI no: 10.1126/science.1147614

Science 317:1390-1393 (2007)

PubMed id: 17690258

LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake.

Z.Zhou, J.Zhen, N.K.Karpowich, R.M.Goetz, C.J.Law, M.E.Reith, D.N.Wang.

ABSTRACT

Tricyclic antidepressants exert their pharmacological effect-inhibiting the reuptake of serotonin, norepinephrine, and dopamine-by directly blocking neurotransmitter transporters (SERT, NET, and DAT, respectively) in the presynaptic membrane. The drug-binding site and the mechanism of this inhibition are poorly understood. We determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT, NET, and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This binding site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters.

Selected figure(s)

Figure 2.
Fig. 2. Structure of the LeuT-desipramine complex and molecular mechanism of LeuT inhibition by desipramine. (A) Structure shown as ribbon diagram viewed from within the membrane plane. An F[obs] – F[calc] map contoured at 3 is superimposed on the structural model. The EL4 hairpin is colored green, and the rest of the protein pink. The helices TM6 and TM11 are removed for clarity. (B) 2F[obs] – F[calc] map contoured at 1 showing the desipramine-binding site in LeuT, viewed from within the membrane plane. Residues R30, Y108, and F253 form the extracellular gate that separates the leucine substrate from the bound desipramine. (C) Local structural changes of LeuT induced by desipramine binding. The structure with desipramine bound is shown in pink and green, without desipramine binding in cyan and blue. When desipramine binds, the side chain of R30 rotates toward D404 and forms a salt bridge with the latter, and the EL4 hairpin, along with A319 and F320, is pushed toward to the extracellular space. (D) Molecular contacts between LeuT and the bound desipramine molecule. The chemical structure of desipramine is shown together with LeuT residues that are in direct contact with the drug. Residues from the EL4 hairpin are shown in the green box; residues from the rest of the protein are shown in pink boxes.

Figure 3.
Fig. 3. Homology models and electrostatic surface potential of desipramine-binding sites in human SERT, NET, and DAT. (A) Desipramine-binding site in the LeuT-desipamine crystal structure. Homology model and electrostatic surface potential of desipramine-binding site in (B) hSERT, (C) hNET, and(D) hDAT, viewed from within the membrane plane. The equivalent residues of those in LeuT that are in direct contact with desipramine are indicated.

The above figures are reprinted by permission from the AAAs: Science (2007, 317, 1390-1393) copyright 2007.

Figures were selected by the author.