New methods addressing the challenges in membrane protein expression, solubilization and crystallization promise to yield many more atomic structures.
Membrane proteins make up roughly 30% of the proteome, but they are highly underrepresented among atomic structures solved, making up less than 1% of the structures in the Protein Data Bank (PDB). This is not due to a lack of biological importance—indeed, membrane protein receptors make up the bulk of drug targets—but to the technical challenges associated with expressing them in large enough quantities for structural analysis, solubilizing them in appropriate detergents and crystallizing them for structure determination. Even structural genomics efforts, where the goal is to solve representative structures for every protein family, have primarily focused on the 'low-hanging fruit' rather than on more challenging structures such as membrane proteins.
But this is changing as both traditional structural biologists and structural genomics researchers are developing new methods to address the expression, solubilization and crystallization bottlenecks. We are already beginning to see some of the results of these increased efforts. Several landmark papers in 2007 and 2008 reported crystal structures of G protein–coupled receptors (GPCRs), which have been particularly intractable to structure determination. Structural genomics groups such as NYCOMPS (New York Consortium on Membrane Protein Structures) and CSMP (Center for Structures of Membrane Proteins) in the US, as well as several international initiatives, are setting up high-throughput pipelines to streamline the determination of membrane protein structures, though so far these efforts have resulted in only a handful of new structures. Meanwhile, solid-state NMR methods, which avoid the requirement for crystallization, are rapidly advancing, but sensitivity and resolution enhancements are still needed to make this a robust technology.
There is unlikely to be a 'one-size-fits-all' protocol for obtaining membrane protein structures; rather, a series of methods are needed to expand the variety of proteins accessible to structure determination. Over the next few years, we should expect to see many more methodological solutions for handling membrane proteins, as well as many more membrane protein structures in the PDB.
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Doerr, A. Membrane protein structures. Nat Methods 6, 35 (2009). https://doi.org/10.1038/nmeth.f.240
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DOI: https://doi.org/10.1038/nmeth.f.240
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