Capturing proteins in their native environment is

essential for drug discovery, where even subtle

structural changes can determine whether a compound

is effective. Traditional crystallography, however, relies

on static snapshots of cryo-cooled crystals. Now, time-

resolved synchrotron serial crystallography (SSX)

– enabled by ESRF-EBS’s exceptional brilliance

and pulsed beam – allows the study of protein

dynamics at room temperature, revealing changes

closer to their true states in living cells.

Serial crystallography was pioneered at X-ray free-

electron lasers (XFELs) with femtosecond resolution,

but most biological processes occur over longer

periods. At ESRF-EBS beamline ID29, ultrashort

X-ray pulses enable once-unattainable room-

temperature time-resolved studies, extending the

reach of this powerful tool to health research.

CAPTURING PROTEINS IN MOTION

WITH SERIAL CRYSTALLOGRAPHY

In its first application at ID29, SSX determined the

first room-temperature structure of the human

cellular defence enzyme NQO1 bound to NADH,

paving the way to understand NQO1’s mechanisms,

with implications for cancer research. SSX has

also captured key motions and conformations in

the SARS-CoV-2 protein Nsp15, informing future

antiviral strategies.

Looking ahead, a planned next-generation drug

discovery pipeline will integrate SSX and ambient

crystallography with virtual compound screening,

high-throughput crystallisation, automated crystal

harvesting and structure determination, and AI-

driven target analysis. By accelerating structure-

guided drug discovery under near-physiological

conditions, this approach will enable new treatments

to tackle global health challenges ranging from

antimicrobial resistance to emerging pathogens and

ageing-related diseases.

EBS SCIENCE

Functional implications of hexameric dynamics in SARSCoV2 Nsp15

M Sonowal et al Protein Sci 346 e70115 2025

Structural dynamics and functional cooperativity of human NQO1 by ambient temperature

serial crystallography and simulations A Grieco et al Protein Sci 334 e4957 2024

Room-temperature serial synchrotron crystallography at

ESRF beamline ID29 revealed the crystal structures of wild

type left and mutated right SARSCoV2 protein Nsp15

showing how mutations enhance enzymatic activity and

thermal stability to promote viral replication informing

future antiviral strategies Image courtesy of ref 2