6NLE
X-ray structure of LeuT with V269 deletion
Summary for 6NLE
| Entry DOI | 10.2210/pdb6nle/pdb |
| Descriptor | Na(+):neurotransmitter symporter (Snf family), LEUCINE, SODIUM ION, ... (9 entities in total) |
| Functional Keywords | leut, membrane protein |
| Biological source | Aquifex aeolicus (strain VF5) |
| Total number of polymer chains | 1 |
| Total formula weight | 57899.41 |
| Authors | Navratna, V.,Yang, D.,Gouaux, E. (deposition date: 2019-01-08, release date: 2020-01-15, Last modification date: 2024-03-13) |
| Primary citation | Campbell, N.G.,Shekar, A.,Aguilar, J.I.,Peng, D.,Navratna, V.,Yang, D.,Morley, A.N.,Duran, A.M.,Galli, G.,O'Grady, B.,Ramachandran, R.,Sutcliffe, J.S.,Sitte, H.H.,Erreger, K.,Meiler, J.,Stockner, T.,Bellan, L.M.,Matthies, H.J.G.,Gouaux, E.,Mchaourab, H.S.,Galli, A. Structural, functional, and behavioral insights of dopamine dysfunction revealed by a deletion inSLC6A3. Proc.Natl.Acad.Sci.USA, 116:3853-3862, 2019 Cited by PubMed Abstract: The human dopamine (DA) transporter (hDAT) mediates clearance of DA. Genetic variants in hDAT have been associated with DA dysfunction, a complication associated with several brain disorders, including autism spectrum disorder (ASD). Here, we investigated the structural and behavioral bases of an ASD-associated in-frame deletion in hDAT at N336 (∆N336). We uncovered that the deletion promoted a previously unobserved conformation of the intracellular gate of the transporter, likely representing the rate-limiting step of the transport process. It is defined by a "half-open and inward-facing" state (HOIF) of the intracellular gate that is stabilized by a network of interactions conserved phylogenetically, as we demonstrated in hDAT by Rosetta molecular modeling and fine-grained simulations, as well as in its bacterial homolog leucine transporter by electron paramagnetic resonance analysis and X-ray crystallography. The stabilization of the HOIF state is associated both with DA dysfunctions demonstrated in isolated brains of expressing hDAT ∆N336 and with abnormal behaviors observed at high-time resolution. These flies display increased fear, impaired social interactions, and locomotion traits we associate with DA dysfunction and the HOIF state. Together, our results describe how a genetic variation causes DA dysfunction and abnormal behaviors by stabilizing a HOIF state of the transporter. PubMed: 30755521DOI: 10.1073/pnas.1816247116 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.615 Å) |
Structure validation
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