TY - JOUR
T1 - Perspective
T2 - Structure determination of protein-ligand complexes at room temperature using X-ray diffraction approaches
AU - Hough, Michael A. A.
AU - Prischi, Filippo
AU - Worrall, Jonathan A. R.
N1 - Funding Information:
The authors acknowledge their present and past group members and collaborators for many fruitful discussions. We acknowledge the BBSRC (BB/W001950/1; BB/01577X/1; BB/R021015/1) for ongoing funding of our work on enzyme structural biology as well as The Leverhulme Trust (RPG-2014-355).
Publisher Copyright:
Copyright © 2023 Hough, Prischi and Worrall.
PY - 2023/1/23
Y1 - 2023/1/23
N2 - The interaction between macromolecular proteins and small molecule ligands is an essential component of cellular function. Such ligands may include enzyme substrates, molecules involved in cellular signalling or pharmaceutical drugs. Together with biophysical techniques used to assess the thermodynamic and kinetic properties of ligand binding to proteins, methodology to determine high-resolution structures that enable atomic level interactions between protein and ligand(s) to be directly visualised is required. Whilst such structural approaches are well established with high throughput X-ray crystallography routinely used in the pharmaceutical sector, they provide only a static view of the complex. Recent advances in X-ray structural biology methods offer several new possibilities that can examine protein-ligand complexes at ambient temperature rather than under cryogenic conditions, enable transient binding sites and interactions to be characterised using time-resolved approaches and combine spectroscopic measurements from the same crystal that the structures themselves are determined. This Perspective reviews several recent developments in these areas and discusses new possibilities for applications of these advanced methodologies to transform our understanding of protein-ligand interactions.
AB - The interaction between macromolecular proteins and small molecule ligands is an essential component of cellular function. Such ligands may include enzyme substrates, molecules involved in cellular signalling or pharmaceutical drugs. Together with biophysical techniques used to assess the thermodynamic and kinetic properties of ligand binding to proteins, methodology to determine high-resolution structures that enable atomic level interactions between protein and ligand(s) to be directly visualised is required. Whilst such structural approaches are well established with high throughput X-ray crystallography routinely used in the pharmaceutical sector, they provide only a static view of the complex. Recent advances in X-ray structural biology methods offer several new possibilities that can examine protein-ligand complexes at ambient temperature rather than under cryogenic conditions, enable transient binding sites and interactions to be characterised using time-resolved approaches and combine spectroscopic measurements from the same crystal that the structures themselves are determined. This Perspective reviews several recent developments in these areas and discusses new possibilities for applications of these advanced methodologies to transform our understanding of protein-ligand interactions.
KW - X-ray crystallography
KW - time-resolved
KW - ambient temperature
KW - spectroscopy
KW - protein-ligand complexes
UR - http://www.scopus.com/inward/record.url?scp=85147441022&partnerID=8YFLogxK
U2 - 10.3389/fmolb.2023.1113762
DO - 10.3389/fmolb.2023.1113762
M3 - Article
SN - 2296-889X
VL - 10
JO - Frontiers in Molecular Biosciences
JF - Frontiers in Molecular Biosciences
M1 - 1113762
ER -