An Insoluble Problem?

The challenges of crystallizing membrane proteins—and how they’re being overcome.

| 4 min read

Register for free to listen to this article
Listen with Speechify
0:00
4:00
Share

Computer artwork of a G protein-coupled receptor in the lipid bilayer of a plasma membraneMEDI-MATION LTD / PHOTO RESEARCHERSMembrane proteins represent only a handful of the total number of protein structures defined to date. Yet these proteins, which represent nearly 40 percent of all known proteins, including receptors, channels, and signaling molecules, are essential for cell communication and their malfunctions are implicated in many diseases. Structure-based design is one powerful way of developing drugs tuned to the precise actions and minimal side effects required for effective treatments. X-ray crystallography—still the only general method for solving the atomic structures of proteins of any size—has been hampered by the extreme difficulty of preparing and crystallizing pure membrane proteins.

The problem is a practical one: hydrophilic proteins, such as those in the cytoplasm, can form crystals in solution relatively easily, but membrane proteins also have hydrophobic parts that buoy the protein in the lipid layer. To maintain their shape, these lipid-loving domains must be surrounded by components that resemble the natural membrane—a requirement that makes it difficult to grow well-diffracting crystals. However, an array of technical advances over the last 2 years has advanced our ability to determine these structures.

Advances are the result of developments at multiple steps in the crystallization process. One example comes from Raymond Stevens and colleagues at the Scripps Research Institute who discovered that lipids were essential for determining the structure of a G protein-coupled receptor (GPCR) that responds ...

Interested in reading more?

Become a Member of

The Scientist Logo
Receive full access to more than 35 years of archives, as well as TS Digest, digital editions of The Scientist, feature stories, and much more!
Already a member? Login Here
3D illustration of a gold lipid nanoparticle with pink nucleic acid inside of it. Purple and teal spikes stick out from the lipid bilayer representing polyethylene glycol.
February 2025, Issue 1

A Nanoparticle Delivery System for Gene Therapy

A reimagined lipid vehicle for nucleic acids could overcome the limitations of current vectors.

View this Issue
Enhancing Therapeutic Antibody Discovery with Cross-Platform Workflows

Enhancing Therapeutic Antibody Discovery with Cross-Platform Workflows

sartorius logo
Considerations for Cell-Based Assays in Immuno-Oncology Research

Considerations for Cell-Based Assays in Immuno-Oncology Research

Lonza
An illustration of animal and tree silhouettes.

From Water Bears to Grizzly Bears: Unusual Animal Models

Taconic Biosciences
Sex Differences in Neurological Research

Sex Differences in Neurological Research

bit.bio logo

Products

Photo of a researcher overseeing large scale production processes in a laboratory.

Scaling Lentiviral Vector Manufacturing for Optimal Productivity

Thermo Fisher Logo
Collage-style urban graphic of wastewater surveillance and treatment

Putting Pathogens to the Test with Wastewater Surveillance

An illustration of an mRNA molecule in front of a multicolored background.

Generating High-Quality mRNA for In Vivo Delivery with lipid nanoparticles

Thermo Fisher Logo
Tecan Logo

Tecan introduces Veya: bringing digital, scalable automation to labs worldwide