Cryo-EM in the pharmaceutical industry

See what your peers are saying about cryo-EM

Since the beginning of the Resolution Revolution, there is a growing enthusiasm for cryo-EM, and it shows no sign of relenting. Pioneering contributions to protein structure determination continue to roll out at an unprecedented pace. A growing number of pharmaceutical companies are partnering with us to realize the benefits of cryo-EM. The articles below highlight why your peers chose to invest in cryo-EM.

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"Cryo-EM is transforming structural biology, allowing us to study many target proteins for the first time and gain new mechanistic insights to help guide future drug design.”

Dr. Chris Phillips, Associate Director of Structural Biology, IMED Biotech Unit, AstraZeneca

"Cryo-electron microscopy has really come on in leaps and bounds in the last few years. One of the requirements of X-ray crystallography is that you have to form crystals. With cryo-EM you don’t, which is a big advantage.”

Dr. Harren Jhoti, Founder, CEO, Astex Pharmaceuticals

"This represents a new era in imaging of proteins in humans with immense implications for drug design.”

— Francis Collins, MD, PhD, NIH Director

"The requirement of X-ray crystallography is that you need to obtain a diffracting crystal to get atomic resolution. That has been a big hurdle if you’re working on challenging targets. Almost every target we’re working on now is very challenging.”

— Dr. Seungil Han, Associate Research Fellow, Pfizer, Groton, CT

“Cryo-EM is positioned to become an even more useful tool in structural biology and cancer drug development… This latest finding provides a tantalizing possibility for advancing effective drug development.”

Dr. Douglas Lowy, Director, USA National Cancer Institute

Cryo-EM Webinars

Webinars

Hear directly from cryo-EM experts

Webinars are an excellent way to learn more about cryo-EM from a wide variety of experts. Listen to researchers, peers and industry thought-leaders as they discuss questions, challenges and solutions related to biology, drug discovery and drug development. Browse the index of free webinars below for topics and/or speakers.

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Scientific publications

Cryo-EM success in the pharmaceutical industry

Want to learn how your drug discovery can benefit from cryo-EM? Learn from your peers' successes. The benefits of this method have been proven in publications from pharmaceutical companies, showing how cryo-EM delivers previously unattainable structural insights needed to accelerate drug discovery.

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Scientific Publications

The following recent publications provide proof of how cryo-EM delivered critical structural insights in different disease areas for a wide range of drug targets. In several cases, cryo-EM provided the insight that was unattainable with other methods, thus accelerating the path to drug discovery.

Cryo-EM structure is vital for the development of potent bispecific antibodies.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20–30% of breast cancer tumors and is associated with a more aggressive disease, higher recurrence rate, and increased mortality. Trastuzumab and pertuzumab are HER2 receptor blockers and have become the standard of care for the treatment of HER2-positive breast cancer. Adding these monoclonal antibodies to the treatment regimen of HER2-positive breast cancer has changed the paradigm for treatment in that form of cancer. The effectiveness of their synergistic activity has been well validated in research as well as in clinical practice.

Objective

Gain structural insight into the synergistic activity of the ternary complex HER2-trastuzumab-pertuzumab.

Benefits of cryo-EM

  • Instrumental in gaining better understanding of synergistic activity.
  • Key insights for the design of bispecific molecules with potentially greater clinical efficacy.
  • Cryo-EM insights complement X-ray crystallography.

Cryo-EM Structure of HER2-trastuzumab-pertuzumab Complex; Hao Y, Yu X, Bai Y, McBride HJ, Huang X (2019), PLoS ONE 14(5): e0216095, Published: May 1, 2019

Cryo-EM complements crystallography in unraveling selective sodium channel blockers.

Voltage-gated sodium (Nav) channels are targets of disease mutations, toxins, and therapeutic drugs. Mutations in Nav channel subtypes are associated with migraines, epilepsy, pain, and cardiac and muscle paralysis syndromes. Channel blockers lack subtype selectivity and have not been well understood.

Objective

Determine key structural templates to design selective Nav channel antagonists using spider protoxin-II (ProTx2).

Benefits of cryo-EM

  • Cryo-EM analysis independently validated the crystallographic structural model of the receptor site.
  • Crystallographic structure took many years to solve. Soaking in compounds was not successful, so cryo-EM was the ultimate choice.
  • Cryo-EM structure supports mechanistic interpretation of ProTx2 complex shifting the activation of Nav and pharmacologically stabilizing the closed-channel state.
Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin

Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin; Xu et al., 2019, Cell 176, 702–715, Published: February 7, 2019

Cryo-EM reveals structure of viral epitope, enabling development of new therapies.

Voltage-gated sodium (Nav) channels are targets of disease mutations, toxins, and therapeutic drugs. Mutations in Nav channel subtypes are associated with migraines, epilepsy, pain, and cardiac and muscle paralysis syndromes. Channel blockers lack subtype selectivity and have not been well understood.

Objective

Identify complex binding site of the virus capsid protein, which was not possible with crystallography due to the complex’s quaternary structure.

Benefits of cryo-EM

  • Cryo-EM reveals the quaternary nature of viral epitope and unravels potent modality for inhibiting polyomavirus infection in kidney transplant recipients and other immunocompromised patients.
Human Memory B Cells Harbor Diverse Cross-Neutralizing Antibodies against BK and JC polyomaviruses

Human Memory B Cells Harbor Diverse Cross-Neutralizing Antibodies against BK and JC polyomaviruses; Lindner et al., 2019, Immunity 50, 668–676, 2019, Published: February 26, 2019

Cryo-EM provides insight in clinical mutations of Friedreich’s ataxia.

Iron-sulfur clusters (ISC), located in the mitochondria matrix, are five-protein complexes containing the cysteine desulfurase that is activated by frataxin (FXN). Deficiency in FXN leads to Friedreich’s ataxia (FRDA), a genetic neurodegenerative disorder that results in cardiological symptoms, loss of limb sensation, locomotion symptoms, impaired speech, and neurological damage.

Objective

Determine complex structure to find out how FXN stabilizes ISC; guide FRDA clinical mutations.

Benefits of cryo-EM

  • Structure of FXN-bound human complex is one of very few reported cryo-EM structures of < 200 kDa and < 3.5 Å resolution for both membrane and soluble proteins.
  • Cryo-EM is applied here to a clinically-relevant target that remain intractable for X-ray crystallography.
Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism

Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism, Nicholas G. Fox, et al., Nature Communications 10, Article number: 2210 (2019), Published: May 17, 2019

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