Relationships between Th1 or Th2 iNKT cell activity and structures of CD1d-antigen complexes: meta-analysis of CD1d-glycolipids dynamics simulations.
A number of potentially bioactive molecules can be found in nature. In particular, marine organisms are a valuable source of bioactive compounds. The activity of an α-galactosylceramide was first discovered in 1993 via screening of a Japanese marine sponge (Agelas mauritanius). Very rapidly, a synthetic glycololipid analogue of this natural molecule was discovered, called KRN7000. Associated with the CD1d protein, this α-galactosylceramide 1 (KRN7000) interacts with the T-cell antigen receptor to form a ternary complex that yields T helper (Th) 1 and Th2 responses with opposing effects. In our work, we carried out molecular dynamics simulations (11.5 µs in total) involving eight different ligands (conducted in triplicate) in an effort to find out correlation at the molecular level, if any, between chemical modulation of 1 and the orientation of the known biological response, Th1 or Th2. Comparative investigations of human versus mouse and Th1 versus Th2 data have been carried out. A large set of analysis tools was employed including free energy landscapes. One major result is the identification of a specific conformational state of the sugar polar head, which could be correlated, in the present study, to the biological Th2 biased response. These theoretical tools provide a structural basis for predicting the very different dynamical behaviors of α-glycosphingolipids in CD1d and might aid in the future design of new analogues of 1.
Intestinal Biotech Development, Faculté de Médecine, Lille, France; Laboratoire de Chimie Thérapeutique EA4481, Université Lille 2, Lille, France.
Xavier
X
Laurent
Laboratoire de Chimie Thérapeutique EA4481, Université Lille 2, Lille, France.
Nicolas
N
Renault
Laboratoire de Chimie Thérapeutique EA4481, Université Lille 2, Lille, France.
Amaury
A
Farce
Laboratoire de Chimie Thérapeutique EA4481, Université Lille 2, Lille, France; Institut de Chimie Pharmaceutique Albert Lespagnol EA4481, Université Lille 2, Lille, France.
Philippe
P
Chavatte
Institut de Chimie Moléculaire de Reims UMR CNRS 7312, University of Reims Champagne-Ardenne, Reims, France.
Eric
E
Hénon
D000818:Animals; D055610:Antigens, CD1d / Q000737:chemistry* / Q000378:metabolism*; D006017:Glycolipids / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D056004:Molecular Dynamics Simulation; D055611:Natural Killer T-Cells / Q000737:chemistry*; D018417:Th1 Cells / Q000737:chemistry*; D018418:Th2 Cells / Q000737:chemistry*; D013816:Thermodynamics
D055610:Antigens, CD1d; D006017:Glycolipids