Structural biology (cryo-EM CRO)

01Overview and value chain

Markers: [EC: PDB / wwPDB validation + FSC 0.143 gold standard | OECD: Genomics & bioinformatics | Regulator: FDA (USA), EMA (EU), NMPA (China)]

Cryo-electron microscopy (cryo-EM) has turned macromolecular structure determination into a B2B contract-research pipeline for structure-based drug design (SBDD). It vitrifies proteins in a thin film of amorphous ice and reconstructs an atomic 3D map from thousands of low-dose 2D projection images, bypassing the years of failed crystallization that X-ray crystallography demanded for membrane proteins such as GPCRs and ion channels. Drug developers now receive drug-design-grade target maps in weeks. The stack runs from vitrification (Thermo Scientific Vitrobot) through 300 kV cryo-TEM (Titan Krios G4) and direct-electron detectors (Falcon 4i / Gatan K3) to computational reconstruction (RELION, cryoSPARC) and atomic model building (Phenix, Coot), delivered as PDB-validated coordinates. Structures feed filings regulated by the FDA, EMA and NMPA, with resolution validated against the Fourier-shell correlation (FSC) 0.143 gold standard and deposited under wwPDB rules. The six organizations in this projection span the hardware backbone (Thermo Fisher, Gatan) and the CRO layer (NanoImaging Services, WuXi AppTec, Proteros, Gandeeva).

Key directions of cryo-EM structural biology as a service:

1. Displacing X-ray crystallography: atomic structures of recalcitrant membrane proteins without crystallization.
2. Drug-design resolution: direct-electron detectors and refinement push maps to roughly 2-3 A, sufficient for rational inhibitor design.
3. Cryo-EM plus machine learning: integration of experimental structures with ML binding prediction for hit finding.
4. Fragment and screening services: cryo-EM coupled to compound-library and fragment screening as a single CRO offering.

Sectoral value chain

[sample prep] ──> [vitrification] ──> [grid screening] ──> [data collection]
                                                          │
                                                (atomic reconstruction)
                                                          │
                                                          ▼
[PDB-validated delivery] <─── [model building] <─────┘

Value chain levels

Cross-cutting technologies of the sector:

• cryo-em: single-particle cryo-EM at 300 kV (Titan Krios) with direct-electron detection.
• x-ray-crystallography: complementary synchrotron crystallography (e.g. ESRF beamlines).
• structure-prediction: AlphaFold models integrated with experimental cryo-EM maps.

02US

The United States leads cryo-EM commercialization, combining the microscope monopoly, dedicated CROs and pharma-funded instrument consortia.

microscope monopoly, dedicated CRO, ML-integrated discovery

• Thermo Fisher Scientific (FEI): the near-monopoly supplier of 300 kV Titan Krios G4 (Cold-FEG, SelectrisX energy filter, Falcon 4i detector), 200 kV Glacios, and the EPU automated-acquisition software.
• NanoImaging Services: a US cryo-EM CRO providing structure determination and lipid-nanoparticle characterization for drug discovery under ISO 9001 / GLP quality systems.
• Gandeeva Therapeutics (Vancouver): the SPOTLIGHT platform integrating cryo-EM with machine-learning binding prediction; in June 2026 it partnered with Zymeworks to accelerate antibody drug discovery.
• Pharma instrument consortia: Pfizer, Amgen and Bristol Myers Squibb pool multi-million-dollar Titan Krios capacity for in-house SBDD pipelines.

03CN

China is running the world’s largest state-funded cryo-EM capacity build-out, aiming to dominate by sheer volume of solved structures.

capacity build-out, CRO integration, domestic TEM

• Westlake University (Hangzhou) and Tsinghua (Beijing): host the world’s largest cryo-EM parks, with Westlake operating more than ten Titan Krios systems on a 24/7 schedule.
• WuXi AppTec (SSE 603259): a top-tier CRO whose Structure Biology Division integrates cryo-EM into its compound-library screening services for global clients.
• Domestic TEM programme: state investment in indigenous 300 kV cryo-TEM systems to reduce dependence on imported Thermo Fisher / FEI instruments.

04EU

The European Union pairs deep structural-biology academe, the leading reconstruction software, and premium CROs with the strictest validation rules.

software leadership, synchrotron + CRO, EMA validation

• RELION (MRC LMB, Cambridge, UK): Sjors Scheres’ package sets the de-facto algorithmic standard for cryo-EM 3D reconstruction worldwide, alongside cryoSPARC.
• ESRF (Grenoble) and EMBL (Heidelberg): shared structural-biology access combining synchrotron crystallography with cryo-EM.
• Proteros biostructures (Germany) and NovAliX (France): premium SBDD CROs offering cryo-EM, fragment screening and ligand-affinity analysis under EU quality systems; Proteros collaborates with Axcelead to serve Japanese clients.

05Leading companies and research institutes

06Tech stack and innovations

The stack spans vitrification physics, direct electron detection and computational reconstruction.

1. Vitrification and 300 kV cryo-TEM:
   • a Vitrobot plunges the grid into liquid ethane at about -160 C, cooling the film fast enough (hundreds of thousands of degrees per second) to freeze water as amorphous ice rather than destructive crystals.
   • the Titan Krios G4 images the grid at 300 kV with a Cold-FEG source, SelectrisX energy filter and Falcon 4i detector, running EPU automated acquisition across 12 autoloader grids.
2. Direct-electron detection and reconstruction:
   • direct detectors (Gatan K3, Falcon 4i) count individual electrons at high frame rates, enabling movie-based motion correction; cryoSPARC and RELION then perform CTF estimation, CNN-based particle picking, 2D classification and 3D refinement to roughly 2-3 A.
3. Model building and PDB validation:
   • Phenix and Coot fit the amino-acid sequence into the density map, and resolution is validated by the FSC 0.143 criterion before wwPDB deposition and B2B coordinate delivery.

07Value chains and production pipelines

Industrial pipeline of a cryo-EM GPCR target structure (PDB-validated)

┌───────────────────────────┐      ┌───────────────────────────┐
│ 1. Sample preparation     │ ───> │ 2. Vitrification          │
└───────────────────────────┘      └───────────────────────────┘
                                                 │
                                                 ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 4. Data collection (Krios)│ <─── │ 3. Grid screening         │
└───────────────────────────┘      └───────────────────────────┘
              │
              ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 5. 3D reconstruction      │ ───> │ 6. Model & PDB delivery   │
└───────────────────────────┘      └───────────────────────────┘

Stage 1: Sample preparation

The GPCR target is expressed in CHO or Sf9 cells and purified by affinity and size-exclusion chromatography to greater than 98% homogeneity.

Stage 2: Vitrification

A few microlitres of protein are applied to a glow-discharged grid in the Vitrobot and plunge-frozen into liquid ethane at about -160 C to form amorphous ice.

Stage 3: Grid screening

Grids are screened on a 200 kV Glacios to assess ice thickness and particle orientation, selecting those with an optimal thin ice layer for data collection.

Stage 4: Data collection

Selected grids are loaded into a 300 kV Titan Krios and EPU automatically collects thousands of high-resolution movies on the Falcon 4i direct detector.

Stage 5: 3D reconstruction

cryoSPARC or RELION performs motion correction, CTF estimation, particle picking, classification and refinement, yielding a density map validated at FSC 0.143.

Stage 6: Model building and PDB delivery

Phenix and Coot fit the atomic model into the map, geometry is validated, and coordinates are deposited to the wwPDB and delivered to the client for rational drug design.