Biology – Page 21

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-HT_1B and of 5-HT_2B, 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.

03.21.2013

the eerie genetic similarity of giant squid

Giant Squid

The giant squid is one of Nature’s most elusive animals. In fact, the first video of the animal in it’s natural habitat was only captured this January. Now a new study of the DNA in squids from around the world shows that they are all the same species. The study appears in PNAS. It looks at the DNA from dead squid that had washed ashore around the world and compared the sequences. It turns out that they are all eerily similar. The species has very little genetic diversity. From Scientific American:

When the researchers looked closely at the mitochondrial DNA of the creatures, they noticed something remarkable. Irrespective of where they came from — be it be it California, Japan, South Africa, New Zealand or somewhere else — the squid were genetically very similar.

In fact, the diversity of Architeuthis is lower than that for any other marine animal, except one — the basking shark Cetorhinus maximus, whose current population is thought to have rebounded from a small number of individuals. At first, says Thomas Gilbert, a geneticist at the University of Copenhagen and an author of the study, “When we found that the global genetic diversity of the giant squid was this low, we figured we had made an error.” But then the team checked their numbers again and saw that they were correct.

The findings not only make it clear that all giant squid around the world are the same species, but they also hint that, like the basking shark, the animals came close to extinction at some point in the not too distant past. The results are published inProceedings of the Royal Society B.

03.18.2013

DNA from HeLa cells is sequenced

HeLa cells viewed under a light microscope

Nature magazine reports that a German lab has sequenced the DNA of HeLa cells. Like cells from most tumors, there are multiple copies of many genes. Excerpt:

Previous work showed that HeLa cells, like many tumors, have bizarre, error-filled genomes, with one or more extra copies of many chromosomes. To get a closer look at these alterations, a team led by Lars Steinmetz, a geneticist at the EuropeanMolecular Biology Laboratory in Heidelberg, Germany, sequenced the popular ‘Kyoto’ version of the cell line and compared the sequence with that of a reference human genome. The team’s results are published in G3.

Steinmetz’s team confirmed that HeLa cells contain one extra version of most chromosomes, with up to five copies of some. Many genes were duplicated even more extensively, with four, five or six copies sometimes present, instead of the usual two. Furthermore, large segments of chromosome 11 and several other chromosomes were reshuffled like a deck of cards, drastically altering the arrangement of the genes.

Without the genome sequence of Lacks’ healthy cells or that of her original tumor, it is difficult to trace the origin of these alterations. Steinmetz points out that other cervical tumors have massive rearrangements on chromosome 11, so the changes in the HeLa cell may have contributed to Lacks’ tumor.

HeLa cells have been the subject of many biological studies as they are easy to culture and replicate very fast. The cells were originally isolated from an African American woman named Henrietta Lacks, and have been cultured for over 60 years. There is also a fascinating book about the origin of these cells called The Immortal Life of Henrietta Lacks.

GOLLYGEE!

Category: Biology (page 21 of 63)

a death receptor crystal structure

the eerie genetic similarity of giant squid

DNA from HeLa cells is sequenced