Cryo-EM Core
Overview
Cryo-EM Core and the David Van Andel Advanced Cryo-Electron Microscopy Suite
The David Van Andel Advanced Cryo-Electron Microscopy Suite harnesses revolutionary technology to visualize some of life’s smallest — yet most vital — components, including cells and molecular complexes, such as proteins. The Suite encompasses state-of-the-art cryo-electron microscopes (cryo-EM), which are supported by expert staff and a robust high-performance computing cluster with extensive cloud capabilities.
The heart of the Core is the Titan Krios transmission electron microscope, which allows scientists to obtain high-resolution images of cells and molecules in their natural state. The Core also houses a Talos Arctica, often considered the “workhorse” of cryo-EM, and a Tecnai Spirit G2 BioTWIN, which is used for preliminary screening of samples.
The Cryo-EM Core is excited to announced the Cryo-EM Suite is now available for use by external investigators.
For questions about the Suite, please contact Core Manager Dr. Gongpu Zhao via email.

Constructing the Titan Krios
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- 171 studies published from Nov. 1, 2020 to Oct. 1, 2021
- 68 studies in high-impact journals from Nov. 1, 2020-Oct. 1, 2021
- 41 clinical trials launched
The David Van Andel Advanced Cryo-Electron Microscopy Suite is an internal facility that offers a range of comprehensive cryo-electron microscopy services along with consulting and training to VAI investigators.
The Cryo-EM Core is excited to announced the Cryo-EM Suite is now available for use by external investigators.
Microscopes
Primary use: Data collection
The Titan Krios is a revolutionary, state-of-the-art transmission electron microscope that visualizes cells, proteins and other crucial structures through atomic-resolution 3-D microscopy and cellular tomography. Unlike traditional methods, it does not require samples to be crystallized prior to imaging, saving time and resources while also capturing the target in its natural state.
Capabilities
- 3-D cryo-electron microscopy
- 2-D electron crystallography
- Single particle analysis
- Dual-axis cellular tomography
Specifications
- 80–300 kV operating range
- Gatan Quantum 967 LS imaging filter
- Post-GIF Gatan K3 direct detection camera
- Pre-GIF Ceta 16M camera
- Automated loading for up to 12 samples
- Ultra-stable Schottky field emitter gun
- Three-lens condenser system for parallel sample illumination
- Digital system for remote operation
- Volta phase plate, live image processing
Primary use: Cryo-EM grid screening and data collection
Considered to be the workhorse of VAI’s Cryo-EM Core, the Talos Arctica is a transmission electron microscope that provides high-resolution and high-throughput 2-D and 3-D imaging of frozen, hydrated biological components, including cells, organelles and proteins.
Capabilities
- 3-D cryo-electron microscopy
- 2-D electron crystallography
- Single-particle analysis
Specifications
- 200 kV FEG transmission electron microscope
- Automated loading for up to 12 samples
- Falcon 3EC direct electron detector
- Ceta 16M camera
- K2 direct detection camera
Primary use: Sample screening
The Tecnai Spirit G2 BioTWIN is a flexible 120kV microscope mainly used for screening negatively stained samples.
Capabilities
- Negative-stain screening
- High-contrast, high-resolution imaging
Specifications
- 20–120 kV operational range
- Gatan Orius 830 CCD camera
- Auto-Gun and automatic tuning
- Smart Tracking Position System
Linux workstations are an indispensable part of the cryo-EM image processing pipeline. The Core has three Linux workstations (Silicon Mechanics Workform 2000.v6) dedicated to cryo-EM analysis that are reserved for core users.
Specifications
- CPU: Intel Xeon E5-2620. 8 cores, hyperthreading, 20 MB cache, 14 nm, 85W
- Ram: 128GB DDR4-2400 ECC registered
- GPU: NVIDIA GeForce GTX 1080 Founders Edition with 8 GB GDDR5X
- Disk: Two 6TB drives in a RAID1 mirror
Software
- Linux Centos 7.3 OS with GNOME
- Relion
- EMAN2
- Pymol
Specifications
- CPU: 2 x Intel Xeon Scalable Gold 5220R, 2.2GHz (24-Core, HT, 2666 MT/s) 150W
- Ram: 768GB PC4-23400 2933MHz
- GPU: 5 x NVIDIA GeForce RTX 3090 TURBO 24G
- Disk: One 16TB SSD
Software
- Cryosparc Liv
Other Instrumentation
- Plasma cleaner: Gatan Solarus Model 950
- Plunge freezers: FEI Vitrobot Mark IV
- Carbon coater: HHV BT150
FAQs
Cryo-EM is short for cryo-electron microscopy, a technique that allows scientists to see tiny molecules down to 1/10,000th the width of a human hair. Although cryo-EM techniques have been around since the mid-1980s, recent advances in technology have led to a scientific revolution, giving scientists the ability to obtain more detailed images of cells, viruses and molecules in their natural state than ever before. In 2015, cryo-EM was named Nature’s Method of the Year.
Structural biology focuses on the shape of the molecules that make up a living organism. As many in the field say, structure is function, meaning that the architecture of a molecule directly informs its role and how it does its job.
Cryo-EM allows scientists to more precisely see proteins and other important structures without many of the constraints posed by traditional methods.
To put its impact in context, in 2007 fewer than 10 molecular structures at less than 5 angstroms (a very tiny unit of measurement) were reported in the literature. Thanks to improvements in cryo-EM technology, by 2015 that number had shot up to nearly 200 (Egelman EH et al; 2016).
Remember, structure informs function. A better understanding of the architecture of cells and molecules gives scientists important insight that allows for the development of new preventative measures, diagnostics and therapies for an untold number of diseases and health problems.
A classic example is that of the key and the lock. If scientists know what the lock looks like, they can develop a key to fit it. In much the same way, if they know what a virus looks like, they are much better equipped to develop a drug that can combat it.
Publications containing work performed by VAI’s Cryo-EM Suite are asked to follow these guidelines in their acknowledgements:
- Acknowledge contributions by The David Van Andel Advanced Cryo-Electron Microscopy Suite by name in the manuscript.
- Consider authorship for more significant intellectual and planning contributions.
- Notify Core staff of successful publications and awarded grant applications. This assists in tracking and maintaining institutional records, which help inform the Suite’s quality services.
HIGHLIGHTED PEER-REVIEWED PUBLICATIONS
Li H*, Burgie S*, Gannam ZTK, Li H#, Vierstra R.D#. (2022). Plant phytochromes are asymmetric dimers with unique signaling potential. Nature.
* Co-first authors
# Co-corresponding authors
Zang F, Georgescu RE, Yao NY, O’Donnell ME*, Li H*. (2022). DNA is loaded through the 911 DNA checkpoint clamp in the opposite direction of the PCNA clamp. Nat Struc Mol Biol.
* Co-corresponding authors
Dykstra H, Fisk C, LaRose C, Waldhart A, Meng X, Zhao G, Wu N. 2021. Mouse long-chain acyl-CoA synthetase 1 is active as a monomer. Arch Biochem Biophys 700:108773.
Du M, Yuan Z, Werneburg GT, Henderson NS, Chauhan H, Kovach A, Zhao G, Johl J, Li H, Thanassi DG. 2021. Processive dynamics of the usher assembly platform during uropathogenic Escherichia coli P pilus biogenesis. Nat Commun 12(1):5207.
Yu H, Haja DK, Schut GJ, Wu CH, Meng X, Zhao G, Li H, Adams MWW. 2020. Structure of the respiratory MBS complex reveals iron-sulfur cluster catalyzed sulfane sulfur reduction in ancient life. Nat Commun 11(1):5953.
Xing C, Zhuang Y, Xu TH, Feng Z, Zhou XE, Chen M, Wang L, Meng X, Xue Y, Wang J, Liu H, McGuire TF, Zhao G, Melcher K, Zhang C, Xu HE, Xie XQ. 2020. Cryo-EM structure of the human cannabinoid receptor CB2-Gi signaling complex. Cell 180(4):645–654.e13.
Zhuang Y, Liu H, Zhou EX, Kumar Verma R, de Waal PW, Jang W, Xu TH, Wang L, Meng X, Zhao G, Kang Y, Melcher K, Fan H, Lambert NA, Xu E, Zhang. 2020. Structure of formylpeptide receptor 2-Gi complex reveals insights into ligand recognition and signaling. Nat Commun 11(1):885.
Xu TH, Liu M, Zhou XE, Liang G, Zhao G, Xu HE, Melcher K, Jones PA. 2020. Structure of nucleosome-bound DNA methyltransferases DNMT3A and DNMT3B. Nature 586(7827):151–155.
Bai L, Kovach A, You Q, Hsu HC, Zhao G, Li H. 2019. Autoinhibition and activation mechanisms of the eukaryotic lipid flippase Drs2p-Cdc50p. Nat Commun 10:4142.
Kim JY, Yeom J, Zhao G, Calcaterra H, Munn J, Zhang P, Kotov N. 2019. Assembly of gold nanoparticles into chiral superstructures driven by circularly polarized light. J Am Chem Soc 141(30):11739–11744.
Yu H, Lupoli TJ, Kovach A, Meng X, Zhao G, Nathan CF, Li H. 2018. ATP hydrolysis-coupled peptide translocation mechanism of Mycobacterium tuberculosis ClpB. Proc Natl Acad Sci U S A 115(41):E9560–E9569.
Hu K, Jastrab JB, Zhang S, Kovach A, Zhao G, Darwin KH, Li H. 2018. Proteasome substrate capture and gate opening by the accessory factor PafE from Mycobacterium tuberculosis. J Biol Chem 293(13):4713–4723.
Du M, Yaun Z, Yu H, Henderson N, Sarowar S, Zhao G, Werneburg GT, Thanassi DG, Li H. 2018. Handover mechanism of the growing pilus by the bacterial outer-membrane usher FimD. Nature.
Kang Y*, Kuybeda O*, de Waal PW*, Mukherjee S, Van Eps N, Dutka P, Zhou XE, Bartesaghi A, Erramilli S, Morizumi T, Gu X, Yin Y, Liu P, Jiang Y, Meng X, Zhao G, Melcher K, Ernst OP, Kossiakoff AA, Subramaniam S, Xu HE. 2018. Cryo-EM structure of human rhodopsin bound to an inhibitory G protein. Nature.
Fan C*, Choi W*, Sun W, Du J#, Lü W#. 2018. Structure of the human lipid-gated cation channel TRPC3. eLife:e36852.
Yu H, Wu CH, Schut GJ, Haja DK, Zhao G, Peters JW, Adams MWW*, Li H*. 2018. Structure of an ancient respiratory system. Cell.
*Co-corresponding authors
Bai L, Wang T, Zhao G, Kovach A, Li H. 2018. The atomic structure of a eukaryotic oligosaccharyltransferase complex. Nature.
Noguchi Y, Yuan Z, Bai L, Schneider S, Zhao G, Stillman B, Speck C, Li H. 2017. Cryo-EM structure of Mcm2-7 double hexamer on DNA suggests a lagging-strand DNA extrusion model. Proc Natl Acad Sci U S A.
Yang M, Chan H, Zhao G, Bahng JH, Zhang P, Kral P, Kotov NA. 2016. Self-assembly of nanoparticles into biomimetic capsid-like nanoshells. Nat Chem doi:10.1038/nchem.2641
Liu C, Perilla JP, Ning J, Lu M, Hou G, Ramalho R, Himes BA, Zhao G, Bedwell GJ, Byeon IJ, Ann J, Gronenborn AM, Prevelige PE, Rousso I, Aiken C, Polenova T, Schulten K, Zhang P. 2016. Cyclophilin A stabilizes the HIV-1 capsid through a novel non-canonical binding site. Nat Commun 7:10714.
Zhao G*, Perilla JR*, Yufenyuy EL*, Meng X, Chen B, Ning J, Ahn J, Gronenborn AM, Schulten K, Aiken C, Zhang P. 2013. Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics. Nature 497:643.
*Featured on Nature cover. This paper was selected as NIGMS Director’s Featured Research Advance in June 2013.
Yeom J, Yeom B, Chan H, Smith KW, Dominguez-Medina S, Bahng JH, Zhao G, Chang W, Chang SJ, Chuvilin A, Melnikau D, Rogach AL, Zhang P, Link S, Král P, Kotov NA 2015. Chiral templating of self-assembling nanostructures by circularly polarized light. Nat Mater 14:66–72.
Meng X*, Zhao G*, Yufenyuy E*, Ke D, Ning J, DeLucia M, Ahn J, Gronenborn AM, Aiken C, Zhang P. 2012. Protease cleavage leads to formation of mature trimer interface in HIV-1 capsid. PLoS Pathog 8(8): e1002886.
*Co-first author
Zhao G, Ke D, Vu T, Ahn J, Shah VB, Yang R, Aiken C, Charlton L, Gronenborn AM, Zhang P. 2011. Rhesus TRIM5α disrupts the HIV-1 capsid at the inter-hexamer interfaces. PLoS Pathog 7(3): e1002009.
Byeon IJL, Meng X, Jung J, Zhao G, Yang R, Shi J, Ahn J, Concel J, Aiken C, Zhang P, Gronenborn AM. 2009. Structural convergence between Cryo-EM and NMR reveals novel intersubunit interactions critical for HIV-1 capsid assembly and function. Cell 139:780.
OTHER PEER-REVIEWED PUBLICATIONS
Ruan Z*, Haley E*, Orozco I*, Sabat M, Myers R, Roth R, Du J#, Lü W#. 2021. Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition. Nat Struct Mol Biol.
Ruan Z*, Osei-Owusu J*, Du J, Qiu Z#, Lü W#. 2020. Structures and pH-sensing mechanism of the proton-activated chloride channel. Nature.
Huang Y, Winkler PA, Sun W, Lü W#, Du J#. 2018. Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium. Nature.
#Co-last authors
Ning J, Erdemci-Tandogan G, Yufenyuy EL, Wagner J, Himes BA, Zhao G, Aiken C, Zandi R, Zhang P. 2016. In vitro protease cleavage and computer simulations reveal the HIV-1 capsid maturation pathway. Nat Commun 7:13689.
Merg AD, Boatz JC, Mandal A, Zhao G, Mokashi-Punekar S, Liu C, Wang X, Zhang P, van der Wel PCA, Rosi NL. 2016. Peptide-directed assembly of single-helical gold nanoparticle superstructures exhibiting intense chiroptical activity. J Am Chem Soc 138(41):13655.
Cassidy C, Himes BA, Alvarez FJ, Ma J, Zhao G, Perilla JR, Schulten K, Zhang P. 2015. CryoEM and computer simulations reveal a novel kinase conformational switch in bacterial chemotaxis signaling. eLife 10.7554/eLife.08419.
Rezikyan A, Jibben ZJ, Rock BA, Zhao G, Koeck FA, Nemanich RF, Treacy MM. 2015. Speckle suppression by decoherence in fuctuation electron microscopy. Microsc Microanal 21(6)1455–1474.
Park J, Nguyen TD, Silveira GQ, Bahng JH, Srivastava S, Zhao G, Sun K, Zhang P, Sharon C, Glotzer SC, Kotov NA. 2014. Terminal supraparticle assemblies from similarly charged protein molecules and nanoparticles. Nat Commun 5:3593.
Song C, Blaber MG, Zhao G, Zhang P, Fry HC, Schatz GC, Rosi NL. 2013. Tailorable plasmonic circular dichroism properties of helical nanoparticle superstructures. Nano Lett 13(7)3256–3261.
Jun S, Zhao G, Ning J, Zhang P. 2013. Correlative microscopy for 3D structural analysis of dynamic interactions. J Vis Exp (76):e50386.
Yang H, Ji X, Zhao G, Ning J, Zhao Q, Aiken C, Gronenborn AM, Zhang P, Xiong Y. 2012. Structural insight into HIV-1 capsid recognition by rhesus TRIM5α. Proc Natl Acad Sci U S A 109(45):18372–18377.
Wang K, Strunk K, Zhao G, Gray JL, Zhang P. 2012. 3D structure determination of native mammalian cells using cryo-FIB and cryo-electron tomography. J Struct Biol 180(2):318–326.
Jun S, Ke D, Debiec K, Zhao G, Meng X, Ambrose Z, Gibson G, Watkins S, Zhang P. 2011. Direct visualization of HIV-1 infection using correlative live-cell microscopy and cryo-EM tomography. Structure 19(11):1573–1581.
Meng X, Zhao G, Zhang P. 2011. Structure of HIV-1 capsid assemblies by cryo-electron microscopy and iterative helical real-space reconstruction. JoVE 54:3041.
Hwang L, Zhao G, Zhang P, Rosi N. 2011. Size-controlled peptide-directed synthesis of hollow spherical gold nanoparticle superstructures. Small 7: doi: 10.1002/smll.201100477.
Song C, Zhao G, Zhang P, Rosi N. 2010. Expeditious synthesis and assembly of sub-100 nm hollow spherical gold nanoparticle superstructures. J Am Chem Soc 132(40):14033–14035.
Zhao G, Treacy MMJ, Buseck PR. 2010. Fluctuation electron microscopy of medium range order in ion-irradiated zircon. Philosoph Mag 90, 4661–4677.
Zhao G, Rougée A, Treacy MMJ, Buseck PR. 2009. Medium-range order in molecular materials: Fluctuation electron microscopy for detecting fullerenes in disordered carbons. Ultramicroscopy 109(2):177–188.
Treacy MMJ, Kumar D, Rougée A, Zhao G, Buseck PR, McNulty I, Fan L, Rau C, Gibson JM. 2008. Glimpsing order within the disarray. J Phys Conf Ser 126(1).
Treacy MMJ, Kumar D, Rougée A, Zhao G, Buseck PR, McNulty I, Fan L, Rau C, Gibson JM. 2007. Probing medium-range structural correlations by fluctuation microscopy. J Phys Condens Matter 19(45).
Zhao G, Zhang Q, Zhang H, Yang G, Tang J, Zhou O, Qin LC. 2006. Field emission of single Cs doped carbon nanotube. Appl Phys Lett 89(26).
Zhao G, Zhang J, Zhang Q, Zhang H, Tang J, Zhou O, Qin LC. 2006. Fabrication and characterization of single nanotube emitters as point electron sources. Appl Phys Lett 89 (19).
Zhang H, Tang J, Zhang Q, Zhao G, Yang G, Zhang J, Zhou O, Qin LC. 2005. Field emission of electron from single LaB6 nanowires. Adv Mater 18, 87.
Zhang H, Zhang Q, Zhao G, Tang J, Zhou O, Qin LC. 2005. Single-crystalline GdB6 nanowire field emitters. J Am Chem Soc 127(38):13120–13121.

Gongpu Zhao, Ph.D.
Manager, Cryo-EM Core

Huilin Li, Ph.D.
Chair and Professor, Department of Structural Biology
Cryo-EM, Structural Biology, DNA Replication and Epigenetics

Xing Meng, Ph.D.
Cryo-Electron Microscopy Core Specialist