Abstract
The translocator protein (TSPO) is an integral membrane protein that interacts with a wide variety of endogenous ligands, such as cholesterol and porphyrins, and is also the target for several small molecules with substantial in vivo efficacy. When complexed with the TSPO-specific radioligand (R)-PK11195, TSPO folds into a rigid five-helix bundle. However, little is known about the structure and dynamics of TSPO in the absence of high-affinity ligands. By means of NMR spectroscopy, we show that TSPO exchanges between multiple conformations in the absence of (R)-PK11195. Extensive motions on time scales from pico- to microseconds occur all along the primary sequence of the protein, leading to a loss of stable tertiary interactions and local unfolding of the helical structure in the vicinity of the ligand-binding site. The flexible nature of TSPO highlights the importance of conformational plasticity in integral membrane proteins.
Original language | English (US) |
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Pages (from-to) | 16555-16563 |
Number of pages | 9 |
Journal | Chemistry - A European Journal |
Volume | 21 |
Issue number | 46 |
DOIs | |
State | Published - Nov 1 2015 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Keywords
- NMR spectroscopy
- dynamics
- function
- membrane proteins
- small molecules
- structure
ASJC Scopus subject areas
- Catalysis
- General Chemistry
- Organic Chemistry