INSIGHTS | PERSPECTIVES
1072 6 MARCH 2015 • VOL 347 ISSUE 6226 sciencemag.org SCIENCE
evade detection of the virus by the human
immune response. The viral component in
the study of Burg et al. is the US28 receptor, one of four chemokine receptors found
in the human cytomegalovirus. This herpesvirus can persist lifelong in an asymptomatic
latent form and is found in 50 to 80% of the
general population. US28 helps the virus to
avoid detection by binding a variety of human chemokines (9). In that sense, it follows
a similar mimicry strategy as related viruses
using the chemokine vMIP-II, except that
in the case of US28, it is the receptor that
shows promiscuous binding.
In contrast to most chemokine receptors,
the viral US28 receptor signals in a ligand-independent (constitutive) manner. This
further enhances pathogenicity of the virus
(10) but is also of more general importance,
because various diseases are attributed to activating GPCR mutations. For example, night
blindness can be inherited through constitutively active mutations in rhodopsin (11). The
way in which US28 stabilizes the G protein
binding site with a unique residue near the
conserved DRY sequence motif is remarkably similar to the effect of a constitutive active mutation in rhodopsin (12). This nicely
illustrates the extent to which important interactions are conserved among GPCRs.
Future molecular dynamics simulations and structural comparisons with the
inactive structures of CCR5 and CXCR4,
guided by common molecular signatures of
the GPCR fold (13), will teach us much of
how chemokine receptors in particular and
GPCRs in general are activated. GPCRs
form the largest group of human drug targets with a series of antiviral and anticancer
drugs specifically targeting chemokine receptors. Understanding the structural basis
of viral chemokine mimicry thus has great
potential to aid the development of small
molecular inhibitors, not only to fight viral
infections but also for treatments against a
wide spectrum of inflammatory and autoimmune diseases. ■
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2. J. S. Burg et al ., Science 347, 1113 (2015).
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7. E. A. Berger, P. M. Murphy, J. M. Farber, Annu.Rev.Immunol.
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8. T. N. Kledal et al ., Science 277, 1656 (1997).
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27, 56 (2006).
11. A.Singhal et al., EMBO Rep. 14,520(2013).
12. X. Deupi et al ., Proc. Natl. Acad. Sci. U. S. A. 109, 119 (2012).
13. A.J.Venkatakrishnan et al., Nature 494,185(2013).
Proteins are the workhorse of life. They assemble the structural elements of the cell, catalyze metabolism, regu- late cellular functions, and even tran- scribe and repair DNA. Many of the proteins’ functions are related to their
physical shape and conformations.
For example, protein-folding problems are responsible for a number
of diseases, including Alzheimer’s
(1). It is no wonder that there has
long been an effort to determine the
structure of proteins. However, only
a small fraction of protein structures
have so far been determined. In most
situations, results from experiments
are not sufficient to build the atomic
model of a protein from scratch.
Even the proteins whose structures
have been determined are usually
purified proteins that are no longer
in their functional environment, so
that the key information on how the
protein changes shape to perform its
innate function can only be inferred.
The solution is to image individual
proteins in living cells in real time as
they go about their business of sustaining life. An important milestone
toward this goal is reported by Shi
et al. on page 1135 of this issue (2).
They show that motions of a segment of a
single protein are inferred by the magnetic
signal of a nuclear spin on a nitroxide spin
label located 10 nm away from a diamond
Magnetic resonance imaging (MRI) is
an established imaging modality for living
systems that is scalable, in principle, down
to atomic resolution. However, to achieve
the resolution needed to monitor structure
and motion in the critical reaction centers
of proteins, a method of readout other than
the usual induction coil is needed. Indeed,
heroic efforts have been made over the
past several decades (3). Using a custom-
designed scanning magnetic probe and a
technique called magnetic resonance force
microscopy (MRFM), imaging of single elec-
tron spins and ensembles of nuclear spins
in a virus molecule down to a resolution of
a few nanometers has been demonstrated.
However, this is still far from single-atom
resolution and requires cryogenic tempera-
tures, which makes its implementation in
living cells problematic.
Several years ago, a new approach to detect the magnetic fields of single nuclei has
emerged. This involves using a laser to read
out the spin state of a special nanomagnetometer probe through a process called
optically detected magnetic resonance
(ODMR). The first of such probes to operate at room temperature was the nitrogen
vacancy (NV) color center in diamond (4,
5). Almost from the start, these NV probes
have been able to see single nuclei in their
local environment inside the diamond crystal. However, it took nearly a decade before
they were successfully used to detect and
locate single electron spins outside of the
diamond lattice (6).
Single proteins under
a diamond spotlight
By Philip Hemmer1 and Carmen Gomes2
A diamond nanomagnetometer is used to probe
conformational changes of a single protein
1Electrical & Computer Engineering Department, Texas A&M
University, College Station, TX 77843-3128, USA. 2Department
of Biological and Agricultural Engineering, Texas A&M
University, College Station, TX 77843-2117, USA.
~10 nm NV center
A diamond probe. Remote nuclear spin detection using a NV
center in diamond and a nitroxide reporter spin label attached to a