Project A07 – Innovative Rosetta algorithms for comparative modeling and docking of GPCRs  

Project A07 focuses on the development of a Rosetta pipeline for comparative modeling and docking of GPCRs based on a combined conformational selection/induced fit paradigm. This novel approach uses RosettaCM to construct GPCR comparative models. It features fully flexible docking of partner proteins with simultaneous construction of loop regions (Aim I). Aim II modifies the RosettaLigand sampling algorithm to dock ensembles of small molecules simultaneously thereby enabling a new scoring function that ranks ligands according to their affinity or biological activity (Aim III). Aim IV benchmarks the overall pipeline.



(Collection of resources used and or created by the project)


Coming soon.

Yang Z, Han S, Keller M, Kaiser A, Bender BJ, Bosse M, Burkert K, Kogler LM, Wifling D, Bernhardt G, Plank N, Littmann T, Schmidt P, Yi C, Li B, Ye S, Zhang R, Xu B, Larhammar D,  Stevens RC, Huster D, Meiler J, Zhao Q, Beck-Sickinger AG, Buschauer  A, Wu B. Structural basis of ligand binding modes at the neuropeptide Y Y1 receptor. Nature. 2018; 556:520-4.

Fu DY, Meiler J. RosettaLigandEnsemble: A Small-Molecule Ensemble-Driven Docking Approach. ACS Omega. 2018; 3:3655-64.

Fu DY, Meiler J. Predictive Power of Different Types of Experimental Restraints in Small Molecule Docking: A Review. J Chem Inf Model. 2018; 58:225-33.

Sliwoski G, Schubert M, Stichel J, Weaver D, Beck-Sickinger AG, Meiler J. Discovery of Small-Molecule Modulators of the Human Y4 Receptor. PLoS One. 2016; 11:e0157146.

Kaiser A, Muller P, Zellmann T, Scheidt HA, Thomas L, Bosse M, Meier R, Meiler J, Huster D, Beck-Sickinger AG, Schmidt P. Unwinding of the C-Terminal Residues of Neuropeptide Y is critical for Y(2) Receptor Binding and Activation. Angew Chem Int Ed Engl. 2015; 54:7446-9.

Wu H, Wang C, Gregory KJ, Han GW, Cho HP, Xia Y, Niswender CM, Katritch V, Meiler J, Cherezov V, Conn PJ, Stevens RC. Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science. 2014; 344:58-64.

Pedragosa-Badia X, Sliwoski GR, Dong Nguyen E, Lindner D, Stichel J, Kaufmann KW, Meiler J, Beck-Sickinger AG. Pancreatic polypeptide is recognized by two hydrophobic domains of the human Y4 receptor binding pocket. J Biol Chem. 2014; 289:5846-59.

Conn PJ, Lindsley CW, Meiler J, Niswender CM. Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders. Nat Rev Drug Discov. 2014; 13:692-708.

Alexander NS, Preininger AM, Kaya AI, Stein RA, Hamm HE, Meiler J. Energetic analysis of the rhodopsin-G-protein complex links the alpha5 helix to GDP release. Nat Struct Mol Biol. 2014; 21:56-63.

Nguyen ED, Norn C, Frimurer TM, Meiler J. Assessment and challenges of ligand docking into comparative models of G-protein coupled receptors. PLoS One. 2013; 8:e67302