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Today, The Visible Embryo is linked to over 600 educational institutions and is viewed by more than 1 million visitors each month. The field of early embryology has grown to include the identification of the stem cell as not only critical to organogenesis in the embryo, but equally critical to organ function and repair in the adult human. The identification and understanding of genetic malfunction, inflammatory responses, and the progression in chronic disease, begins with a grounding in primary cellular and systemic functions manifested in the study of the early embryo.

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Pregnancy Timeline by SemestersFetal liver is producing blood cellsHead may position into pelvisBrain convolutions beginFull TermWhite fat begins to be madeWhite fat begins to be madeHead may position into pelvisImmune system beginningImmune system beginningPeriod of rapid brain growthBrain convolutions beginLungs begin to produce surfactantSensory brain waves begin to activateSensory brain waves begin to activateInner Ear Bones HardenBone marrow starts making blood cellsBone marrow starts making blood cellsBrown fat surrounds lymphatic systemFetal sexual organs visibleFinger and toe prints appearFinger and toe prints appearHeartbeat can be detectedHeartbeat can be detectedBasic Brain Structure in PlaceThe Appearance of SomitesFirst Detectable Brain WavesA Four Chambered HeartBeginning Cerebral HemispheresFemale Reproductive SystemEnd of Embryonic PeriodEnd of Embryonic PeriodFirst Thin Layer of Skin AppearsThird TrimesterSecond TrimesterFirst TrimesterFertilizationDevelopmental Timeline
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Home | Pregnancy Timeline | News Alerts |News Archive March 10, 2014

 

Researchers at the Scripps Research Institute and Vanderbilt University
have achieved an important new understanding of the mGlu1 receptor,
a target for future medicines for the treatment of brain disorders.

Credit: Image by Katya Kadyshevskaya, courtesy of the Scripps Research Institute

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Protein linked to learning, pain, brain disorders

Researchers at The Scripps Research Institute (TSRI) and Vanderbilt University have created the most detailed 3-D picture yet of a membrane protein linked to learning, memory, anxiety, pain and brain disorders such as schizophrenia, Parkinson's, Alzheimer's and autism.


"This receptor family is an exciting new target for future medicines for treatment of brain disorders."

"Our new understanding of how drug-like molecules engage the receptor at an atomic level promises to have a major impact on new drug discovery efforts."


P. Jeffrey Conn, PhD, Lee E. Limbird, professor Pharmacology, director, Vanderbilt Center for Neuroscience Drug Discovery, senior author of the study with Raymond Stevens, PhD, professor, Department of Integrative Structural and Computational Biology at TSRI.


The research focuses on the mGlu1 receptor and was reported in the March 6, 2014 issue of the journal Science.


The mGlu1 receptor helps regulate the neurotransmitter glutamate, and belongs to a superfamily of molecules known as G protein-coupled receptors (GPCRs).

GPCRs sit in the cell membrane and sense various molecules outside the cell, including odors, hormones, neurotransmitters and light.

After binding these molecules, GPCRs trigger a specific response to each within the cell. More than one-third of therapeutic drugs target GPCRs — including allergy and heart medications, drugs that target the central nervous system and anti-depressants.

The Stevens lab's work is focused on determining the structure and function of GPCRs which were not well understood. Now many fundamental breakthroughs are occurring as a result of realizing that GPCRs are complex machines, carefully regulated by cholesterol and sodium.


When the Stevens group decided to pursue the structure of mGlu1 and other key members of the mGlu family, it was natural the scientists reached out to the researchers at Vanderbilt. "They are the best in the world at understanding mGlu receptors," said Stevens. "By collaborating with experts in specific receptor subfamilies, we can reach our goal of understanding the human GPCR superfamily and how GPCRs control human cell signaling."

Colleen Niswender, PhD, director of Molecular Pharmacology and research associate professor of Pharmacology at the Vanderbilt Center for Neuroscience Drug Discovery, also thought the collaboration made sense. "This work leveraged the unique strengths of the Vanderbilt and Scripps teams in applying structural biology, molecular modeling, allosteric modulator pharmacology and structure-activity relationships to validate the receptor structure," she said.


In general, GPCRs are exceedingly flimsy, fragile proteins when not anchored within their native cell membranes. Coaxing them to line up and form crystals, to determine their structures through X-ray crystallography, was a formidable challenge.

The mGlu1 receptor is particularly difficult as one of its domains spans the cell membrane, and the other extends into extracellular space. Moreover, two copies are needed of this multidomain receptor to transmit glutamate's signal across the membrane.


The task was made more difficult because no template existed for mGlu1 from closely related GPCR proteins to guide the researchers.

"mGlu1 belongs to class C GPCRs, of which no structure has been solved before," said TSRI graduate student Chong Wang, a first author of the new study with TSRI graduate student Huixian Wu. "This made the project much harder. We could not use other GPCRs as a template to design constructs for expression and stabilization or to help interpret diffraction data. The structure was so different that old school methods in novel protein structure determination had to be used."

The team proceeded to apply a combination of techniques, including X-ray crystallography, structure-activity relationships, mutagenesis and full-length dimer modeling. At the end of the study, they had achieved a high-resolution image of mGlu1 in complex with one of the drug candidates, as well as a deeper understanding of the receptor's function and pharmacology.

The findings show that mGlu1 possesses structural features both similar to and distinct from those seen in other GPCR classes, but in ways that would have been impossible to predict in advance.


"Most surprising is that the entrance to a binding pocket in the transmembrane domain is almost completely covered by loops, restricting access for binding by allosteric modulators.

"This is very important for understanding the action by allosteric modulator drugs  — and may partially explain difficulties in screening for such drugs.

"The mGlu1 receptor structure now provides a solid platform for much more reliable modeling of closely related receptors, some of which are equally important in drug discovery."

Vsevolod "Seva" Katritch, assistant professor, molecular biology, TSRI and a co-author of the paper.


Abstract
The excitatory neurotransmitter glutamate induces modulatory actions via the metabotropic glutamate receptors (mGlus), which are class C G protein-coupled receptors (GPCRs). We determined the 2.8 Å resolution structure of the human mGlu1 receptor seven-transmembrane (7TM) domain bound to a negative allosteric modulator FITM. The modulator binding site partially overlaps with the orthosteric binding sites of class A GPCRs, but is more restricted compared to most other GPCRs. We observed a parallel 7TM dimer, mediated by cholesterols, suggesting that signaling initiated by glutamate’s interaction with the extracellular domain might be mediated via 7TM interactions within the full-length receptor dimer. A combination of crystallography, structure-activity relationships, mutagenesis, and full-length dimer modeling provides insights on the allosteric modulation and activation mechanism of class C GPCRs.

Authors
Huixian Wu1, Chong Wang1, Karen J. Gregory, Gye Won Han, Hyekyung P. Cho, Yan Xia, Colleen M. Niswender, Vsevolod Katritch, Jens Meiler, Vadim Cherezov, P. Jeffrey Conn, Raymond C. Stevens


In addition to Stevens, Conn, Niswender, Wu, Wang, Katritch and Gregory, other authors of the study, "Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator," included Gye Won Han and Vadim Cherezov of TSRI; and Hyekyung Cho, Yan Xia and Jens Meiler of Vanderbilt University Medical Center.

National Institutes of Health grants that supported the research included GM094618, GM073197, NS031373, NS078262 and MH090192; additional support was provided by the International Rett Syndrome Foundation.