Structural Biology

Structural biology seeks to reveal the three-dimensional architecture and dynamic behaviour of biological macromolecules and their assemblies. By determining atomic and near-atomic models of proteins, nucleic acids and complexes, it defines the spatial relationships of functional groups, binding pockets and catalytic centres. Core experimental techniques include X-ray crystallography, which exploits diffraction by ordered crystals; nuclear magnetic resonance (NMR) spectroscopy, which interrogates molecules in solution via nuclear spin interactions; and cryogenic electron microscopy (cryo-EM), which images frozen-hydrated specimens without requiring crystals. Complementary mass-spectrometric and chemical-labelling methods, such as hydrogen-deuterium exchange, capture conformational flexibility and solvent access at peptide-level resolution. Advances in sample preparation, detectors and computational analysis have extended all approaches toward high throughput, ever-greater resolution and the study of heterogeneous, multi-component machines. The resulting structural insights underpin understanding of enzyme mechanisms, macromolecular recognition, viral entry, membrane transport and signal transduction, and guide the rational design of small-molecule drugs, biologics and engineered enzymes. Integrative strategies combine data from multiple sources with modelling to build atomic models of large assemblies, defining how molecular form enables biological function in health and disease.

Research from Nature Portfolio

Cryo-EM has now captured multiple intermediates of a self-splicing ribozyme, revealing how a group I intron undergoes stepwise conformational transitions. Six reconstructions at near-atomic resolution show coordinated movements of an internal guide sequence, long-range junctions and metal-cofactor positions, completing an atomistic portrait of RNA-only catalysis through transesterification steps.

Hydrogen-deuterium exchange mass spectrometry has been applied to the SARS-CoV-2 spike glycoprotein, mapping conformational shifts among variants. Changes in flexibility of receptor-binding and N‐terminal domains explain why Alpha, Beta and Delta preferentially sample open, ACE2-binding states, whereas Omicron adopts a more closed but fusion-primed ensemble, illuminating the balance between immune evasion and entry competency.

Cryo-EM analysis of microfibril-associated glycoprotein 4 resolved octameric assemblies at 3.6 Å. In the presence of calcium, MFAP4 forms disulfide-linked homodimers that pair into octamers, displaying salt-bridge and hydrophobic networks. Multiple binding surfaces for fibrillin, tropoelastin and integrin receptors define how an extracellular glycoprotein scaffolds elastic-fibre organisation and cell adhesion.

Structural Biology publication trend

The graph below shows the total number of articles in structural biology across all publications each year (not limited to Nature Index journals).

Technical terms

X-ray crystallography: A method that determines atomic arrangements from the pattern of X-rays diffracted by a crystalline sample.

Cryogenic electron microscopy (cryo-EM): A technique in which specimens are vitrified and imaged with an electron beam to reconstruct three-dimensional density maps of macromolecules.

Nuclear magnetic resonance (NMR): An approach that exploits nuclear spin resonances in a strong magnetic field to derive structural and dynamic information in solution.

Hydrogen-deuterium exchange mass spectrometry (HDX-MS): A strategy that measures the exchange of backbone amide hydrogens with deuterium to probe protein flexibility and solvent accessibility.

Conformational ensemble: The collection of interconverting structural states that a macromolecule populates under given conditions.

Resolution: The level of spatial detail in a structural dataset, typically reported in ångströms (Å), that determines the clarity of atomic features.

References

1. Snapshots of the second-step self-splicing of Tetrahymena ribozyme revealed by cryo-EM. Nature Communications (2023).
2. Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein. Nature Communications (2023).
3. Microfibril-associated glycoprotein 4 forms octamers that mediate interactions with elastogenic proteins and cells. Nature Communications (2024).
4. Discovery of natural non-circular permutations in non-coding RNAs. Nucleic Acids Research (2023).
5. Crucial Roles of Two Hydrated Mg2+ Ions in Reaction Catalysis of the Pistol Ribozyme. Angewandte Chemie International Edition (2020).
6. Overall Introduction and Rationale, with View from Computational Biology.