Feb 16, 2022
A "resolution revolution": how cryo-EM accelerates biomedicine and drug discovery
Cryo-electron microscopy, X-ray crystallography and computational methods for high resolution structural characterization of protein
The Structural Biology Platform (SBP) supports FMI scientists with cutting-edge structural biology techniques including cryo-electron microscopy (cryo-EM) and X-ray crystallography. In addition, we assist FMI users with modern computational methods for the analysis of protein structures, model building and final structure validation.
Since 2016, we have been working together with the EM team at Novartis to first establish and then further develop and expand a joint EM facility. The expertise in the EM facility is complemented by the FAIM platform at FMI, bringing scanning electron microscopy competence.
Single-particle cryo-electron microscopy
With the introduction of a new generation of direct electron detectors for transmission electron microscopes, followed by a development of new software for image analysis and increased computational power, we are now in a position to image ice-embedded molecular machines at near-atomic resolution. We use single-particle cryo-electron microscopy (cryo-EM) to reveal structural information and mode of action of pivotal protein complexes. Cryo-EM does not require crystallization and can be applied to protein complexes with a broad range of molecular weights. Dedicated to support FMI research groups, we provide service and training from sample preparation to image analysis.
For several decades, X-ray crystallography has been the standard technique to solve high- resolution structures. X-ray crystallography is an important tool to obtain high-resolution structures of small to medium sized proteins, nucleic acids and small complexes. It complements the accurate analysis of large macromolecular complexes by cryo-EM, which often relies on crystal structures of individual subcomponents. We provide equipment for convenient high-throughput crystal screening and regular synchrotron access in collaboration with Novartis. Our expertise and hands-on support help FMI research groups to carry out successful crystallography projects.
Computational structural biology
We apply cutting-edge computational methods for structure prediction, docking, and molecular dynamics simulations. These methods are often combined with low-resolution experimental information and help to guide further experiments. We also support FMI research groups interested in using these methods independently.
Cloning and protein production
Routine protein purification and cloning based on established protocols are offered as a support to research groups at the FMI. The platform is equipped to maintain E. coli, insect and mammalian cells culture.
Simone Cavadini: Platform head, structural biology
Kozicka Z, Suchyta DJ, Focht V, Kempf G, Petzold G, Jentzsch M, Zou C, Di Genua C, Donovan KA, Coomar S, Cigler M, Mayor-Ruiz C, Schmid-Burgk JL, Häussinger D, Winter GE, Fischer ES, Slabicki M, Gillingham D, Ebert BL, Thomä NH (2023) Design principles for cyclin K molecular glue degraders.Nat Chem Biol. 2023 Sep 7
Michael AK, Stoos L, Crosby P, Eggers N, Nie XY, Makasheva K, Minnich M, Healy KL, Weiss J, Kempf G, Cavadini S, Kater L, Seebacher J, Vecchia L, Chakraborty D, Isbel L, Grand RS, Andersch F, Fribourgh JL, Schübeler D, Zuber J, Liu AC, Becker PB, Fierz B, Partch CL, Menet JS, Thomä NH (2023) Cooperation between bHLH transcription factors and histones for DNA access.Nature. 2023 Jul;619(7969):385-393
Pla-Prats C, Cavadini S, Kempf G, Thomä NH (2023) Recognition of the CCT5 di-Glu degron by CRL4(DCAF12) is dependent on TRiC assembly.EMBO J. 2023 Feb 15;42(4):e112253
Langousis G, Sanchez J, Kempf G, Matthias P (2022) Expression and Crystallization of HDAC6 Tandem Catalytic Domains.Methods Mol Biol. 2023;2589:467-480
Wang L, Moreira EA, Kempf G, Miyake Y, Oliveira Esteves BI, Fahmi A, Schaefer JV, Dreier B, Yamauchi Y, Alves MP, Plückthun A, Matthias P (2022) Disrupting the HDAC6-ubiquitin interaction impairs infection by influenza and Zika virus and cellular stress pathways.Cell Rep. 2022 Apr 26;39(4):110736
Langousis G, Cavadini S, Boegholm N, Lorentzen E, Kempf G, Matthias P (2022) Structure of the ciliogenesis-associated CPLANE complex.Sci Adv. 2022 Apr 15;8(15):eabn0832
Mohamed WI, Schenk AD, Kempf G, Cavadini S, Basters A, Potenza A, Abdul Rahman W, Rabl J, Reichermeier K, Thomä NH (2021) The CRL4DCAF1 cullin-RING ubiquitin ligase is activated following a switch in oligomerization state.EMBO J. 2021 Nov 15;40(22):e108008
Nörpel J, Cavadini S, Schenk AD, Graff-Meyer A, Hess D, Seebacher J, Chao JA, Bhaskar V. (2021) Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture.PLoS Biol. 2021 Jul 23;19(7):e3001344
Shimada Y, Carl SH, Skribbe M, Flury V, Kuzdere T, Kempf G, Bühler M (2021) An enhancer screen identifies new suppressors of small-RNA-mediated epigenetic gene silencing.PLoS Genet. 2021 Jun 22;17(6):e1009645
Bhaskar V, Desogus J, Graff-Meyer A, Schenk AD, Cavadini S, Chao JA (2021) Dynamic association of human Ebp1 with the ribosome.RNA. 2021 Apr;27(4):411-419
Pathare GR, Decout A, Glück S, Cavadini S, Makasheva K, Hovius R, Kempf G, Weiss J, Kozicka Z, Guey B, Melenec P, Fierz B, Thomä NH, Ablasser A (2020) Structural mechanism of cGAS inhibition by the nucleosomeNature. 2020 Nov;587(7835):668-672
Michael AK, Grand RS, Isbel L, Cavadini S, Kozicka Z, Kempf G, Bunker RD, Schenk AD, Graff-Meyer A, Pathare GR, Weiss J, Matsumoto S, Burger L, Schübeler D, Thomä NH (2020) Mechanisms of OCT4-SOX2 motif readout on nucleosomesScience. 2020 Jun 26;368(6498):1460-1465
Schenk AD, Cavadini S, Thomä NH, Genoud C (2020) Live Analysis and Reconstruction of Single-Particle Cryo-Electron Microscopy Data with CryoFLAREJ Chem Inf Model. 2020 May 26;60(5):2561-2569
Bhaskar V, Graff-Meyer A, Schenk AD, Cavadini S, von Loeffelholz O, Natchiar SK, Artus-Revel CG, Hotz HR, Bretones G, Klaholz BP, Chao JA (2020) Dynamics of uS19 C-Terminal Tail during the Translation Elongation Cycle in Human RibosomesCell Rep. 2020 Apr 7;31(1):107473
Rabl J, Bunker RD, Schenk AD, Cavadini S, Gill ME, Abdulrahman W, Andrés-Pons A, Luijsterburg MS, Ibrahim AFM, Branigan E, Aguirre JD, Marceau AH, Guérillon C, Bouwmeester T, Hassiepen U, Peters AHFM, Renatus M, Gelman L, Rubin SM, Mailand N, van Attikum H, Hay RT, Thomä NH (2019) Structural Basis of BRCC36 Function in DNA Repair and Immune RegulationMol Cell. 2019 Aug 8;75(3):483-497.e9
Matsumoto S, Cavadini S, Bunker RD, Grand RS, Potenza A, Rabl J, Yamamoto J, Schenk AD, Schübeler D, Iwai S, Sugasawa K, Kurumizaka H, Thomä NH (2019) DNA damage detection in nucleosomes involves DNA register shiftingNature. 2019 Jul;571(7763):79-84