Odd One Out

Researchers determine structure of unique receptor linked to neurodegeneration

Researchers determine structure of unique receptor linked to neurodegeneration
HMS graduate student and first author Hayden Schmidt describes the strange characteristics of the structure of the sigma-1 receptor, which has been linked to neurodegenerative diseases. Video: Stephanie Dutchen

Sigma-1 isn’t genetically related to any other protein in the human body.

It’s the adopted child of the opioid receptor family, preferring mirror image versions of the drugs that bind to true opioid receptors. 

In the last decade, it’s been linked to neurodegenerative diseases, addiction and pain. Yet researchers know almost nothing about what it looks like or how it works.

Now, a team led by Harvard Medical School biochemists has determined sigma-1’s atomic structure, offering explanations for some of its mysteries and opening the door to examining its potential as a drug target.

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“We know this receptor is important. It’s very highly conserved evolutionarily across vertebrates; it’s involved in human disease; it has pharmacological cross-reactivity against a lot of known drugs. But it’s been a black box,” said Andrew Kruse, assistant professor of biological chemistry and molecular pharmacology at HMS and senior author of the study, published April 4 in Nature.

“Having the structure not only explains a lot of the older pharmacology literature, it also allows us to design much more intelligent experiments to figure out how sigma-1 works at a basic level and potentially exploit it for clinical applications,” he said.

Structural surprises

Sigma-1 was discovered 40 years ago. As its documented roles in pharmacology grew more bizarre and its connections to human disease strengthened, understanding its structure became more pressing. But studying receptors like sigma-1 that live in oily, water-repelling cell membranes is challenging.

The team solved the problem by using a special technique called lipidic cubic phase crystallography, which allowed them to crystallize sigma-1 while it was embedded in a membrane mimicking its natural environment. The technique is popular for studying G protein-coupled receptors, a focus of Kruse’s lab, and is being adopted more widely, he said.

“We’re used to working with proteins that aren’t accommodating,” Kruse explained.

Andrew Kruse walks through the lipidic cubic phase crystallography process step by step. Video: Stephanie Dutchen
Andrew Kruse walks through the lipidic cubic phase crystallography process step by step. Video: Stephanie Dutchen