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Tag: crystallography

04.04.2013

crystal scaffolds

Crystalline sponge with guaiazulene guests (light blue). Image from Nature

Cyrstallographers everywhere will attest to how hard it can be to get some molecules to crystalize. Sometimes, there might not even be enough material there to attempt crystallization. Someone is working on a solution though. C&EN reports that researchers have generated a nanoscale scaffold that captures molecules in pores and allows x-ray crystal data to be collected on samples with as little as 80ng of material. From the magazine:

In X-ray crystallography, X-rays are shot through a single crystal of a compound. How they bounce, or diffract in crystallographic lingo, reveals the structure of the molecule that makes up the crystal. The technique has helped scientists visualize innumerable molecules, including antibiotics, industrial catalysts, and even artificial sweeteners.

A team led by Makoto Fujita, of the University of Tokyo, in Japan, reports it can use porous metal frameworks with large cavities as “crystalline sponges” that soak up guest molecules within their voids, putting the molecules in an ordered array that can be studied via X-ray crystallography (Nature, DOI: 10.1038/nature11990). The technique works on as little as 80 ng of material.

In one example, the researchers used a zinc-based crystalline sponge to soak up just 5 µg of miyakosyne A, a scarce marine natural product with a central methyl group that had defied stereochemical assignment. Using their crystal-free crystallographic technique, the team was able to identify the compound’s stereochemistry.

Check out the full study at Nature.

03.22.2013

a death receptor crystal structure

Illustrations of the binding pockets of 5-HT1B and 5-HT2b Serotonin receptors. Image from Science via C&EN.

Receptors for the neurotransmitter serotonin are popular drug targets. Drugs that target these receptors are used to treat problems like depression and migraine headaches. Serotonin receptors are also the targets of some psychedelic drugs like LSD and mescaline.

There are at least 14 subtypes of serotonin receptors known. Most of the drugs that target one subtype of serotonin receptor will also target the others. This is usually not a problem except in the case of one type called 5-HT2B. This receptor is called the death receptor because activating it can cause heart problems that will lead to death. This receptor is to be avoided.

Chemical & Engineering News brings word of two crystal structures that might help drug developers better avoid activating the 5-HT2B subtype of receptors:

Help will come from new crystal structures of 5-HT1B and of 5-HT2B, each bound to the migraine drugs ergotamine and dihydroergotamine (Science,DOI: 10.1126/science.1232807 and DOI: 10.1126/science.1232808). The findings provide a blueprint for designing more selective 5-HT inhibitors.

The team behind the structures includes Raymond C. Stevens, a chemistry and molecular biology professor at Scripps Research Institute, La Jolla, Calif.; Bryan L. Roth, a pharmacology professor at the University of North Carolina; H. Eric Xu, director of the Center for Structural Biology & Drug Discovery at Van Andel Research Institute in Grand Rapids, Mich., and Hualiang Jiang, a professor at the Shanghai Institute of Materia Medica.

This is major news for our field,” adds Kathryn A. Cunningham, a professor in the pharmacology and toxicology department at the University of Texas Medical Branch. “The structures were solved for the receptor-ligand cocrystals, which provides important insights into how the receptors work.”

The importance of selectivity was most infamously illustrated in the 1990s by the obesity treatment Fen-Phen (fenfluramine-phentermine). Both molecules targeted 5-HT receptors, but they weren’t selective enough. Unbeknown to scientists, they also bound to the death receptor, 5-HT2B, triggering sometimes-fatal cardiovascular side-effects. Fen-Phen’s withdrawal from the market was the largest in history and cost its manufacturer, Wyeth, billions of dollars in damages.

Check out the original research here and here.

03.22.2012

how opioids work

A morphine-like molecule (in yellow) binds to a pocket in the mu-opiod receptor (in blue). Image from Science News. Provided by the Kobilka Lab at Stanford University.

Ever wonder how opioid drugs work their magic? Drugs like morphine, codeine and heroin? Lots of people have. And two groups of scientists, one  at Stanford and one at Scripps, have made progress in figuring out how they ease pain and cause addiction. The Stanford group crystallized a morphine like molecule with the mu opioid receptor protein. Excerpted from Sceince News:

Many of today’s most powerful painkillers work by switching on one of these proteins, called the mu opioid receptor. But the relief this provides comes at a price. Derivatives of opium, such as morphine and codeine, are addictive and can cause breathing problems and constipation.

To better understand how these drugs work, an international team of researchers for the first time crystallized a small morphinelike molecule attached to a mu receptor — a technically difficult task that requires isolating the pair of molecules without unsticking them from each other. X-rays revealed how one molecule lined up with the other.

This study has limitations though: the molecule they crystallized deactivates the receptor instead of activating it like morphine or codeine, so the interactions they are looking at might not necessarily be the same interactions that are important in easy pain or causing addiction.

The Scripps group looks at a different opioid receptor, the kappa-opioid receptor. Their crystal structure reveals the binding interactions of the experimental drug JDTic with kappa-opioid receptor. This receptor is linked to stress responses moreso than pain relief, so it should tell a different story than the other.

Exciting stuff! I can’t wait to get my hands on the actual research papers.

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