B6: Structural elucidation of the GPCR allosteric machine

We apply complementary in silico and in vitro structural biology methods to obtain insights into the dynamic modulation of G protein coupled receptors by ligands or signal transducers. To address the key question of G protein coupling specificity we investigate the role of the open cytoplasmic crevice of the human β2-adrenoceptor or bovine rhodopsin in selective binding of Gi, Gs or arrestins. We use native and mutant peptides derived from the key binding sites of the Gα subunit (GαCT) or arrestin (finger loop, ArrFL) to elucidate their role in the selective (on/off) switching of downstream signaling pathways. Our long term goal is to obtain high affinity variants of GαCT and ArrFL, enabling modelling, MD simulations and protein X-ray crystallography of complexes of R* with Gi or arrestin.

Selected Publications

Szczepek M, Beyrière F, Hofmann KP, Elgeti M, Kazmin R, Rose A, Bartl FJ, von Stetten D, Heck M, Sommer ME, Hildebrand PW, Scheerer P
Crystal structure of a common GPCR-binding interface for G protein and arrestin.
Nat Commun 2014; 5(4801):doi: 10.1038/ncomms5801.
Budkevich, T, Giesebrecht, J, Ramrath, D, Mielke, T, Ismer J, Hildebrand, P, Tung, C-S, Nierhaus, KH, Sanbonmatsu, KY and Spahn, CM
Regulation of the Mammalian elongation cycle by subunit rolling: a eukaryotic-specific ribosome rearrangement.
Cell 2014; 158(1):121-131.
Rose AS, Elgeti M, Zachariae U, Grubmüller H, Hofmann KP, Scheerer P, Hildebrand PW
Position of Transmembrane Helix 6 Determines Receptor G Protein Coupling Specificity.
J Am Chem Soc 2014; 136(32):11244-11247.
Elgeti M, Rose AS, Bartl FJ, Hildebrand PW, Hofmann KP, Heck M
Precision vs Flexibility in GPCR signaling.
J Am Chem Soc 2013; 21(135):12305-12.
Yong Ju Kim, Klaus Peter Hofmann, Oliver P. Ernst, Patrick Scheerer, Hui-Woog Choe & Martha E. Sommer
Crystal structure of pre-activated arrestin p44.
Nature 2013; 497(7447):142-6.
Ismer, J., Rose, A., Goede, A., Johanna K. S. Tiemann, Rother, K. and Hildebrand, P.W.
Voronoia4RNA – A database of atomic packing densities of RNA structures and their complexes.
Nucleic Acids Res 2013; 41:D280-4. doi: 10.1093/nar/gks1061.
Ramrath D, Yamamoto H, Rother K, Wittek D, Pech M, Mielke T, Loerke J, Scheerer P, Ivanov P, Teraoka Y, Shpanchenko O, Nierhaus K, Spahn CM
The complex of tmRNA-SmpB and EF‐G on translocating ribosomes.
Nature 2012; 485(7399):526-9.
Kaden,D., Harmeier,A., Weise,C., Munter,L.M., Althoff,V., Rost,B.R., Hildebrand,P.W., Schmitz,D., Schaefer,M., Lurz,R., et al.
Novel APP/Aβ mutation K16N produces highly toxic heteromeric Aβ oligomers.
EMBO Mol Med 2012; 7:647-59.
Piechnick, R., Ritter, E., Hildebrand, P.W., Ernst, O.P., Scheerer, P., Hofmann, K. and Heck, M.
Effect of channel mutations on the uptake and release of the retinal ligand in opsin.
Proc Natl Acad Sci U S A 2012; 109(14):5247-52.
Botev A, Munter LM, Wenzel R, Richter L, Althoff V, Ismer J, Gerling U, Weise C, Koksch B, Hildebrand PW, Bittl R, Multhaup G
The Amyloid Precursor Protein C-Terminal Fragment C100 Occurs in Monomeric and Dimeric Stable Conformations and Binds gamma-Secretase Modulators.
Biochemistry 2011; 50:828-835.
Fritsch J, Scheerer P, Frielingsdorf S, Kroschinsky S, Friedrich B, Lenz O, Spahn CM
The crystal structure of an oxygen-tolerant hydrogenase uncovers a novel iron-sulphur centre.
Nature 2011; 479(7372):249-52.
Elgeti M, Kazmin R, Heck M, Morizumi T, Ritter E, Scheerer P, Ernst OP, Siebert F, Hofmann KP, Bartl FJ
Conserved Tyr223(5.58) plays different roles in the activation and G-protein interaction of rhodopsin.
J Am Chem Soc 2011; 133(18):7159-65.
Muhs M, Yamamoto H, Ismer J, Takaku H, Nashimoto M, Uchiumi T, Nakashima N, Mielke T, Hildebrand PW, Nierhaus KH, Spahn CM
Structural basis for the binding of IRES RNAs to the head of the ribosomal 40S subunit. Nucleic Acids Res..
Nucleid Acids Research 2011; 39(12):5264-75.
Hui-Woog Choe, Yong Ju Kim, Jung Hee Park, Takefumi Morizumi, Emil F. Pai, Norbert Krauß, Klaus Peter Hofmann, Patrick Scheerer & Oliver P. Ernst
Crystal structure of metarhodopsin II.
Nature 2011 Mar 9; 471(7340):651-5.