6ZBV

Inward-open structure of human glycine transporter 1 in complex with a benzoylisoindoline inhibitor and sybody Sb_GlyT1#7

6ZBV の概要

• エントリーDOI: 10.2210/pdb6zbv/pdb
• 関連するPDBエントリー: 6ZPL
• 分子名称: Sodium- and chloride-dependent glycine transporter 1,Sodium- and chloride-dependent glycine transporter 1, Sybody Sb_GlyT1#7, [5-fluoranyl-6-(oxan-4-yloxy)-1,3-dihydroisoindol-2-yl]-[5-methylsulfonyl-2-[2,2,3,3,3-pentakis(fluoranyl)propoxy]phenyl]methanone (3 entities in total)
• 機能のキーワード: secondary active transport, neurotransmitter-sodium symport, amino acid transport, slc6a9, inward open state, inhibitor bound complex, membrane protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 78672.67

構造登録者

Shahsavar, A.,Stohler, P.,Bourenkov, G.,Zimmermann, I.,Siegrist, M.,Guba, W.,Pinard, E.,Sinning, S.,Seeger, M.A.,Schneider, T.R.,Dawson, R.J.P.,Nissen, P. (登録日: 2020-06-09, 公開日: 2021-03-17, 最終更新日: 2024-11-20)

主引用文献

Shahsavar, A.,Stohler, P.,Bourenkov, G.,Zimmermann, I.,Siegrist, M.,Guba, W.,Pinard, E.,Sinning, S.,Seeger, M.A.,Schneider, T.R.,Dawson, R.J.P.,Nissen, P.
Structural insights into the inhibition of glycine reuptake.
Nature, 591:677-681, 2021

PubMed Abstract: The human glycine transporter 1 (GlyT1) regulates glycine-mediated neuronal excitation and inhibition through the sodium- and chloride-dependent reuptake of glycine. Inhibition of GlyT1 prolongs neurotransmitter signalling, and has long been a key strategy in the development of therapies for a broad range of disorders of the central nervous system, including schizophrenia and cognitive impairments. Here, using a synthetic single-domain antibody (sybody) and serial synchrotron crystallography, we have determined the structure of GlyT1 in complex with a benzoylpiperazine chemotype inhibitor at 3.4 Å resolution. We find that the inhibitor locks GlyT1 in an inward-open conformation and binds at the intracellular gate of the release pathway, overlapping with the glycine-release site. The inhibitor is likely to reach GlyT1 from the cytoplasmic leaflet of the plasma membrane. Our results define the mechanism of inhibition and enable the rational design of new, clinically efficacious GlyT1 inhibitors.

PubMed: 33658720
DOI: 10.1038/s41586-021-03274-z

実験手法

X-RAY DIFFRACTION (3.4 Å)