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Subject: NIH RESEARCHERS PROVIDE DETAILED VIEW OF BRAIN PROTEIN STRUCTURE

U.S. Department of Health and Human Services NATIONAL INSTITUTES OF HEALTH
NIH News National Institute of Neurological Disorders and Stroke (NINDS)
<http://www.ninds.nih.gov/> For Immediate Release: Thursday, October 11,
2012

CONTACT: Christopher Thomas, NINDS, 301-496-5751,
<e-mail:[log in to unmask]>

NIH RESEARCHERS PROVIDE DETAILED VIEW OF BRAIN PROTEIN STRUCTURE Results may
help improve drugs for neurological disorders

Researchers have published the first highly detailed description of how
neurotensin, a neuropeptide hormone which modulates nerve cell activity in
the brain, interacts with its receptor.  Their results suggest that
neuropeptide hormones use a novel binding mechanism to activate a class of
receptors called G-protein coupled receptors (GPCRs).  

"The knowledge of how the peptide binds to its receptor should help
scientists design better drugs," said Dr. Reinhard Grisshammer, a scientist
at the NIH's National Institute of Neurological Disorders and Stroke (NINDS)
and an author of the study published in Nature.

Binding of neurotensin initiates a series of reactions in nerve cells.
Previous studies have shown that neurotensin may be involved in Parkinson's
disease, schizophrenia, temperature regulation, pain, and cancer cell
growth.

Dr. Grisshammer and his colleagues used X-ray crystallography to show what
the receptor looks like in atomic detail when it is bound to neurotensin.
Their results provide the most direct and detailed views describing this
interaction which may change the way scientists develop drugs targeting
similar neuropeptide receptors.

X-ray crystallography is a technique in which scientists shoot X-rays at
crystallized molecules to determine a molecule's shape and structure.  The
X-rays change directions, or diffract, as they pass through the crystals
before hitting a detector where they form a pattern that is used to
calculate the atomic structure of the molecule.  These structures guide the
way scientists think about how proteins work.

Neurotensin receptors and other GPCRs belong to a large class of membrane
proteins which are activated by a variety of molecules, called ligands.
Previous X-ray crystallography studies showed that smaller ligands, such as
adrenaline and retinal, bind in the middle of their respective GPCRs and
well below the receptor's surface.  In contrast, Dr. Grisshammer's group
found that neurotensin binds to the outer part of its receptor, just at the
receptor surface.  These results suggest that neuropeptides activate GPCRs
in a different way compared to the smaller ligands.

Forming well-diffracting neuropeptide-bound GPCR crystals is very difficult.
Dr. Grisshammer and his colleagues spent many years obtaining the results on
the neurotensin receptor.  During that time Dr. Grisshammer started
collaborating with a group led by Dr. Christopher Tate, Ph.D. at the MRC
Laboratory of Molecular Biology, Cambridge, England.  Dr. Tate's lab used
recombinant gene technology to create a stable version of the neurotensin
receptor which tightly binds neurotensin.  Meanwhile Dr. Grisshammer's lab
employed the latest methods to crystallize the receptor bound to a short
version of neurotensin.

The results published today are the first X-ray crystallography studies
showing how a neuropeptide agonist binds to neuropeptide GPCRs.
Nonetheless, more work is needed to fully understand the detailed signaling
mechanism of this GPCR, said Dr. Grisshammer.

This study was supported by NINDS; the National Institute of Diabetes and
Digestive and Kidney Diseases; Protein Production Facility of the New York
Consortium on Membrane Protein Structure, New York City; and the MRC
Laboratory of Molecular Biology.

NINDS <http://www.ninds.nih.gov> is the nation's leading funder of research
on the brain and nervous system.  The NINDS mission is to reduce the burden
of neurological disease -- a burden borne by every age group, by every
segment of society, by people all over the world. 

About the National Institutes of Health (NIH): NIH, the nation's medical
research agency, includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. NIH is the primary federal
agency conducting and supporting basic, clinical, and translational medical
research, and is investigating the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and its programs,
visit <www.nih.gov>.

 NIH...Turning Discovery into Health
--------------
REFERENCE: White et al., "Structure of the agonist-bound neurotensin
receptor." Nature, published online October 10, 2012. DOI:
10.1038/nature11558 ###

This NIH News Release is available online at:
<http://www.nih.gov/news/health/oct2012/ninds-11.htm>.

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