Brian Kobilka talks with
ScienceWatch.com and answers a few questions about
this month's Fast Breaking Paper in the field of Biology
& Biochemistry. The author has also sent along
images of their work.
Article Title: High-resolution crystal structure of
an engineered human beta(2)-adrenergic G protein-coupled
receptor
Authors: Cherezov, V;Rosenbaum, DM;Hanson, MA;Rasmussen,
SGF;Thian, FS;Kobilka, TS;Choi, HJ;Kuhn, P;Weis,
WI;Kobilka,
BK;Stevens, RC
Journal: SCIENCE
Volume: 318
Issue: 5854
Page: 1258-1265
Year: NOV 23 2007
* Stanford Univ, Sch Med, Dept Cellular & Mol Physiol,
Stanford, CA 94305 USA.
(addresses have been truncated)
Why do you think your paper is highly
cited?
For at least two reasons:
1. Structural determination of membrane proteins in general, and human
membrane proteins in particular, has proven very difficult. Therefore the
paper is of interest from the perspective of membrane protein structural
biology.
2. The ß2 adrenergic receptor (ß2AR) is representative of the
large family of G protein-coupled receptors (GPCRs). GPCRs represent the
largest family of receptors for hormones and neurotransmitters, and
therefore the largest group of targets for pharmaceutical therapeutics.
These proteins are consequently very interesting from a physiologic
perspective, and there is hope that a better understanding of GPCR
structure will lead to more efficient development of drugs for a very broad
spectrum of diseases.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
This paper provides the first high-resolution picture of a
hormone-activated G protein-coupled receptor. Crystallization of these
membrane proteins is very challenging. The discovery was achieved by the
application of several complementary methods. This paper and the companion
Science article describe the use of protein engineering,
lipid-based crystallography screens, and new microfocus X-ray technology
that were required to obtain this structure. We were also able to obtain a
structure of an unmodified ß2AR in complex with an antibody fragment,
although at lower resolution (Rasmussen et al., Nature
2007. See Figure. )
Would you summarize the significance of your paper in
layman's terms?
The paper presents a high-resolution three-dimensional picture of a
receptor for adrenaline. The adrenaline receptor is structurally similar to
receptors for serotonin, dopamine, histamine, and many other hormones and
neurotransmitters. The technology developed and applied to obtain the
adrenaline receptor structure may be applied to obtain structures for other
receptors. These structures may be useful for the development of more
effective drugs for a broad spectrum of diseases.
How did you become involved in this research, and were
there any problems along the way?
I became interested in G protein-coupled receptors during my clinical
training in internal medicine from 1981-84. In 1984 I joined the laboratory
of Dr. Robert Lefkowitz at Duke University, and was part of the team that
cloned the ß2 adrenergic receptor in 1986. Since that time I have
been working to understand the structural basis of the function of this
protein.
This paper provides the first
high-resolution picture of a hormone-activated G
protein-coupled receptor.
The major challenges to obtaining the crystal structure were to develop
methods to produce and purify sufficient quantities of high-quality
receptor protein for crystallography trials, and to develop methods to
stabilize this otherwise fragile and flexible membrane protein and
facilitate crystal formation.
Where do you see your research leading in the
future?
We are currently working on obtaining a structure of the active state of
the ß2 adrenergic receptor in complex Gs, the G protein that becomes
activated by the receptor and propagates the signal to other cellular
proteins. We are also working on methods to study the dynamic properties of
G protein-coupled receptors.
Crystal structures provide very useful information, but these structures
represent only a snapshot of the many conformations that the protein
assumes during its normal function in the cell. To fully understand how
these proteins work, we need to characterize this dynamic behavior.
Do you foresee any social or political implications for
your research?
Only to the extent that GPCR structures help to develop more effective
drugs at lower cost.
Brian Kobilka, M.D.
Professor
Departments of Molecular and Cellular Physiology and Medicine
Stanford University School of Medicine
Stanford, CA, USA
References:
Rasmussen SGF, Choi HJ, Rosenbaum, DM, Kobilka TS, Thian FS, Edwards PC,
Burghammer M, Rratnala VRP, Sanishvili R, Fischetti RF, Schertler GFX, Weis
WI, Kobilka BK, "Crystal structure of the human beta 2 adrenergic G protein
coupled receptor," Nature 450: 383-7, 2007.