Molecular Blueprints

Check out the latest crop of high-resolution structures and how they inform biological function.

By | March 27, 2012

image: Molecular Blueprints Poppy pods from the plant Papaver somniferum—the source of many opiates, including morphine and codeine. Researchers recently published the high-resolution structures of two of the body's opioid receptors.Flickr, trenarren

Poppy pods from the plant Papaver somniferum—the source of many opiates, including morphine and codeine. Researchers recently published the high-resolution structures of two of the body's opioid receptors. FLICKR, TRENARREN

Opioid receptors revealed
Name: Kappa-opioid receptor (?-OR) and mu-opioid receptor (µ-OR)

The mu opioid receptor, the target of opium, may partner with itself when bound to a morphine-like drug.
The mu opioid receptor, the target of opium, may partner with itself when bound to a morphine-like drug.
KOBILKA LAB

The brain’s opioid receptors regulate powerful neurological effects such as sedation, analgesia, depression, and euphoria by serving as the targets of a wide range of endogenous molecules such as endorphins and opiate drugs like morphine, codeine, oxycodone, and heroin. Although their detailed atomic structures have been highly sought after for decades, these cell membrane proteins have long evaded X-ray crystallography—a process that requires them to be purified in high quantities and then crystallized before their structures can be illuminated by X-ray crystallography. Now two independent research teams have produced high-resolution atomic structures of the mu-opioid receptor (µ-OR), which recognizes morphine and codeine, and the kappa-opioid receptor (?-OR), the only known receptor for Salvinorin A, a powerful, naturally occurring hallucinogen produced by the plant Salvia divinorum.

In both cases, the trick was to crystallize the receptors while they were bound to stabilizing molecules. Among other things, the structures reveal wide, gaping binding sites, which help explains the “promiscuity” of most opiate drugs, which are often capable of binding multiple types of opiate receptors. Detailed knowledge of the receptors’ binding sites will be useful in developing drugs that treat anxiety, chronic pain, and depression, as well as drug addiction.

A. Manglik, et. al., “Crystal structure of the µ-opioid receptor bound to a morphinan antagonist,” Nature, doi:10.1038/nature10954, 2012. H. Wu, et. al., “Structure of the human ?-opioid receptor in complex with JDTic,” Nature, doi:10.1038/nature10939, 2012.

The human enterovirus
Name: Human enterovirus 71 (EV71)

Researchers have determined the 3.8-angstrom resolution crystal structure of the human enterovirus 71—an RNA virus member of the picornavirus family that may lead to paralysis and encephalitis in infants and young children. The structure of the virus revealed a small hydrophobic “pocket” molecule that likely becomes exposed prior to the release of genetic material during the infection process. Drugs that target this exposed molecule, the authors suggest, could potentially be effective in neutralizing the virus.

P Plevka, et. al., "Crystal structure of human enterovirus 71," Science, DOI:10.1126/science.1218713, 2012.

Rescuing ribosomes
Name: The tmRNA and YaeJ ribosome-rescuing complexes

When a ribosome reaches the end of a prematurely truncated or defective mRNA sequence, it becomes stuck. In bacteria, these stalled ribosomes are rescued by transfer-messenger RNA (tmRNA), hybrid molecules that function both as transfer and messenger RNAs. The rescuing process involves an elongation factor called Tu (EF-Tu), which delivers the tmRNA to the site of the ribosome that receives new amino acids for building protein sequences, and the protein SmpB, which latches onto the tmRNA-EF-Tu complex and binds them to the ribosome. By determining the crystal structure of a ribosome from a Gram negative bacterium bound to EF-Tu, SmpB, and a tmRNA fragment, researchers confirmed that the tmRNA complex helps stalled ribosomes become unstuck by filling in for both the anticodon region of tRNA, as well as the truncated mRNA itself. The study also suggests that the complex is able to recognize only stalled ribosomes by sensing the empty spots in the mRNA channel of the ribosome left open by the truncated mRNA molecule.

In a parallel study, a different group of researchers determined the structure of an alternative ribosome-rescuing complex in bacteria that employs a 140-amino acid protein called YaeJ instead of tmRNA. The 3.2-angstrom-resolution structure of the YaeJ system revealed that, like the tmRNA system, YaeJ rescues stalled ribosomes by binding to a partially empty mRNA channel.

C. Neubauer, et. al., "Decoding in the absence of a codon by tmRNA and SmpB in the ribosome," Science, 335: 1366-9, 2012.MG Gagnon, et. al., “Structural basis for the rescue of stalled ribosomes: structure of YaeJ bound to the ribosome,” Science, 335:1370-2, 2012.

Bacterial nucleoside transporter
Name: Vibrio cholerae concentrative nucleoside transporter (vcCNT)

Nucleoside transporters, as their name suggests, are membrane proteins that shuttle nucleosides into and out of cells. Because they also help transport nucleoside-derived drugs, such as certain antiviral and anticancer drugs, across cell membranes, understanding the details of their function will inform better drug design. To this end, researchers have published a high-resolution crystal structure of Vibrio cholerae’s concentrative nucleoside transporter, which uses sodium ions to transport the nucleosides. The study identifies the putative nucleoside- and sodium-binding sites and suggests that the transporter exists as a trimer. ZL Johnson, et. al., “Crystal structure of a concentrative nucleoside transporter from Vibrio cholerae at 2.4?Å,” Nature, doi:10.1038/nature10882, 2012.

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Avatar of: garryjeet

garryjeet

Posts: 1

March 28, 2012

Realy-realy super great pics. everytime i loose my motivation in training -i remember these pics-- it works and the motivation is soon back
 

Avatar of:

Posts: 0

March 28, 2012

Realy-realy super great pics. everytime i loose my motivation in training -i remember these pics-- it works and the motivation is soon back
 

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