Spectroscopic solution: NMR accesses membrane protein structures
- Published: Oct 1, 2011
- Author: David Bradley
- Channels: NMR Knowledge Base
Membrane proteins mediate so much of the information flow between cells and their surroundings. Understanding their molecular structure will inevitably give scientists insights into function and form as well as providing targets for novel pharmaceuticals when these proteins go awry.
Unfortunately, membrane proteins are notoriously difficult to study with X-ray crystallography, not least because they rarely form suitable crystals, if at all. High-resolution NMR spectroscopy, however, can probe protein structure in solution and even in situ and has a unique role to play in research into membrane proteins and drug discovery.
Writing in the journal Current Opinion in Chemical Biology, CongBao Kang and Qingxin Li of the Agency for Science, Technology and Research, Singapore, explain how the term "membrane protein" usually refers to a subset of proteins attached to or associated with the membrane of a cell or an organelle. Almost one in three of cellular proteins are integral membrane proteins (IMPs) in which at least one part of the protein is embedded in the plasma membrane. It is these proteins that are involved in critical biological processes such as signal transduction and ion transportation; among them G protein-coupled receptors (GPCRs) and ion channels account for more than half of the targets for current pharmaceutical agents. This makes them not only important in terms of understanding the action of the majority of drugs but also potential targets for new drug discovery.
The team explains how recent advances in solution NMR spectroscopy have been used to determine the structures of membrane proteins that are either difficult to express, cannot be crystallised or which undergo conformational denaturation on extracting from the membrane and so offer only a distorted view of the active form of the protein. To address this latter problem, researchers have developed membrane-mimicking systems that allow solution NMR to be recorded on the proteins in a simulated real-life environment but without the clutter and noise associated with actual cells.
NMR has become a powerful tool, when used in conjunction with model membrane systems it is even more powerful. The researchers also point out that used in parallel with X-ray crystallography, powder diffraction, or synchrotron studies it can be more powerful still. Initially, NMR was limited to low-molecular weight proteins and to cytosolic proteins, but the technology and methodology is advancing rapidly. "With novel libraries specifically targeted at NMR screening (such as libraries containing 19F-labeled compounds) and the greater availability of structural information of membrane proteins, NMR will very probably play an important role in drug discovery," the team concludes.
The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.