Towards understanding structural and dynamical determinants of G protein inhibition - rational design of novel subtype specific G-protein inhibitors
Physical Chemistry of Molecules, Liquids and Interfaces, Biophysical Chemistry
Final Report Abstract
The main results of this project can be summarized as follows: (1) Novel FR900359-based analogs from natural sources, synthetic cyclic peptides as well as all so-far known Gαq inhibitors were in-silico analyzed in a comprehensive way and their binding site recognition was deciphered. (2) This led us to the conclusion, that YM/FR might not be suitable scaffolds for developing novel inhibitors as all approaches failed to derive novel molecules with improved activity towards Gq or any activity towards Gs or Gi. (3) For the comprehensive structure-activity-relationship study, a combined docking and simulation approach was developed. (4) The solution NMR structures of FR, YM, some novel FR-based analogs and some synthetic cyclic peptides were elucidated in water and some organic solvents. (5) The conformation of FR in water is similar to the conformation of YM in water. This waterderived conformation significantly differs from the conformation of both molecules in organic solvents as well as the conformation thought to be present in the crystal structure 3ah8, which served as a base for the rational design of novel inhibitors. (6) Refit of the electron density map of pdb 3ah8 with the water-derived YM structure revealed that this structure also represents a valid solution of the crystal structure. (7) A simulation approach was developed, which allows the observation of the opening and closing motion in-silico. (8) Using the above-mentioned simulation approach, we elucidated the mechanism of G protein inhibition on an atomistic level. (9) The same simulation approach together with pseudo free energy calculations revealed, that the water-derived YM conformation has a higher affinity to the Gq binding site and is most likely the conformation, which is bound to the protein.
Publications
- “Deciphering specificity determinants for FR900359-derived Gq alpha based on computational and structure-activity studies“, 2018, ChemMedChem
R. Reher, T. Kühl, S. Annala, T. Benkel, D. Kaufmann, B. Nubbemeyer, J. P. Odhiambo, P. Heimer, C. A. Bäuml, S. Kehraus, M. Cruesemann, E. Kostenis, D. Tietze*, G. König and D. Imhof
(See online at https://doi.org/10.1002/cmdc.201800304) - "Rational design of a heterotrimeric G protein α subunit with artificial inhibitor sensitivity", 2019, J. Biol. Chem.
D. Malfacini, J. Patt, S. Annala, K. Harpsøe, F. Eryilmaz, R. Reher, M. Crüsemann, W. Hanke, H. Zhang, D. Tietze, D. Gloriam, H. Bräuner-Osborne, K. Strømgaard, G. König, A. Inoue, J. Gomeza, and E. Kostenis
(See online at https://doi.org/10.1074/jbc.RA118.007250) - “Structural and dynamical basis of G protein inhibition by YM-254890 and FR900359: an inhibitor in action”, 2019, J. Chem. Inf. Model.
D. Tietze, Desireé Kaufmann, A. A. Tietze, A. Voll, R. Reher, G. König, F. Hausch
(See online at https://doi.org/10.1021/acs.jcim.9b00433)
