Structural biology—the science of visualizing the molecular machinery of life at the atomic level—has revolutionized our understanding of how living organisms function.
Evolution of structural biology techniques over time
By revealing the intricate three-dimensional shapes of proteins, DNA, and other biomolecules, this field provides the fundamental blueprint for understanding health and disease. Recent breakthroughs have accelerated progress at an unprecedented pace, transforming not just how we see biology, but how we treat everything from cancer to COVID-19.
The journey of structural biology began in earnest when scientists first glimpsed the structure of myoglobin, an oxygen-storing protein in muscle cells 6 .
Kendrew & Perutz received the Nobel Prize for determining the first protein structures using X-ray crystallography 6 .
Kurt Wüthrich was awarded the Nobel Prize for developing nuclear magnetic resonance spectroscopy for determining the 3D structure of biological macromolecules in solution 6 9 .
Dubochet, Frank, and Henderson received the Nobel Prize in Chemistry for developing cryo-electron microscopy 6 9 .
Today, we are in the era of in situ structural biology, where the goal is to observe molecular machines at work inside their native cellular environment 6 .
Improvement in resolution of structural biology techniques over time
Primary technique for decades
Studied proteins in solution
Cryo-EM has become the tool of choice for tackling some of biology's most challenging targets, particularly integral membrane proteins 1 . These proteins are embedded in the cell's fatty membrane and act as crucial gatekeepers and signal receivers. They are the targets of over 50% of modern drugs, yet are notoriously difficult to study because removing them from their membrane environment often destroys their natural shape.
Scientists used Cryo-EM to solve the structure of GPR55, a mysterious class A G-protein coupled receptor (GPCR) 1 .
Researchers developed "Rigid-Fabs" to stabilize small proteins (15-20 kDa) for Cryo-EM study 1 .
A perfect example of Cryo-EM's power is a recent study from the University of Cincinnati, where scientists visualized, for the first time, the complex between two key proteins: the enzyme ADAM17 and its regulatory partner, iRhom2 2 .
Comparison of structural biology techniques
| Technique | Strength | Nobel Year |
|---|---|---|
| X-ray Crystallography | High-resolution details | 1962 |
| NMR Spectroscopy | Protein dynamics | 2002 |
| Cryo-EM | Large complexes | 2017 |
If Cryo-EM gave us new eyes, then Artificial Intelligence (AI) has given us a new brain. The impact of AI-powered tools like AlphaFold 2 and RoseTTAFold has been so profound that their developers were awarded the 2024 Nobel Prize in Chemistry 1 . These systems can predict a protein's 3D structure from its amino acid sequence with astonishing accuracy, often rivaling experimental methods.
The synergy between AI and traditional experiments is creating powerful new workflows 1 :
Impact of AI on structural biology research efficiency
AI screens for interactions across the entire proteome
Identifies new protein complexes for therapeutic targeting
The frontier of structural biology is moving from taking isolated snapshots to making full-length movies of molecular life inside the cell. This is being powered by the integration of multiple techniques 6 .
By pairing Cryo-ET with super-resolution fluorescence microscopy, scientists can find specific proteins and then zoom in with electrons to see ultra-structure 6 .
Computational power has advanced to build dynamic 3D models of entire cells, simulating the environment where biomolecules operate 6 .
This integrated approach is crucial for developing next-generation therapies like Targeted Protein Degraders (TPDs) 1 . These "molecular destroyers" recruit the cell's own garbage disposal system to eliminate disease-causing proteins. Structural biology is essential for designing these complex drugs.
Revealed activation mechanism of an orphan GPCR by its native lipid ligand 1 .
Visualized the "re-entry loop" essential for inflammatory signaling 2 .
Determined 3D architecture of amyloid plaques in human tissue 1 .
Timeline of recent structural biology breakthroughs
From the first blurry glimpse of myoglobin to the ability to watch molecular machines at work inside a cell, structural biology has undergone a profound transformation. Driven by the twin engines of Cryo-EM and AI, the field is no longer just about observing nature—it's about actively designing solutions. The lessons from its history are clear: by continuing to develop sharper tools to see the invisible, we unlock the potential to cure the incurable. The atomic blueprints we generate today are the foundation for the life-saving medicines of tomorrow.