molecule of the month: interferons - RCSB Protein Data Bank

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About the
RCSB PDB Molecule of the Month
Using selected molecules from the PDB
archive, each feature includes an
introduction to the structure and function of
the molecule, a discussion of its relevance to
human health and welfare, and
suggestions for viewing and
accessing further details.
The RCSB PDB Molecule of the Month is
read by students, teachers, and scientists
worldwide at www.pdb.org.
This August 2010 edition was written and
illustrated by David S. Goodsell
(RCSB PDB and The Scripps
Research Institute).
MOLECULE OF THE MONTH:
INTERFERONS
doi: 10.2210/rcsb_pdb/mom_2010_8
Virus Alert
Interferons are secreted by infected cells to
warn their neighbors, and once stimulated,
cells of the immune system secrete interferons
as part of their viral surveillance. Interferons
are small proteins that bind to receptors on the
cell surface. This signal is transmitted into the
cells and leads to production of hundreds of
proteins involved in viral defense. Several types
of interferons are made by our cells. Interferon-
alpha and interferon-beta, shown here from
PDB entries
1itf
and
1au1
, are the most
common types, and are made by most types of
cells, especially cells of the immune system.
They send a basic signal to stop growing and
focus on defense. Interferon-gamma, shown
here from PDB entry
1rfb
, is secreted primari-
ly by T-cells, and sends signals that tune the
response of the immune system.
Interferon Therapy
When interferon was first discovered, it seemed
to be the perfect treatment for fighting viral
infection. Since it also slows down the growth
of cells, it also seemed like a perfect treatment
for stopping the uncontrolled growth of cancer
cells. Interferons are very specific, though, and
only interferon from human cells or other
primates is effective for treatment. So wide-
spread use and testing needed to wait until the
1980s, when methods for genetic engineering
progressed enough to allow production of
recombinant interferon. Today, recombinant
interferon is used to treat hepatitis and other
viruses, multiple sclerosis, and a few types of
cancer. However, since it has such an extreme
effect on cells, it causes significant side effects,
and it is currently only used in specialized cases.
Our cells have many defenses
against viruses. When cells are
infected, they build enzymes that
slow protein synthesis, and thus
also slow down viral growth, and
they build enzymes to chop up
double-stranded RNA, which is
made primarily by viruses. Infected
cells also alert the immune system
by displaying pieces of the virus on
their surfaces. In the worst cases,
infected cells make the ultimate
sacrifice and destroy themselves by
apoptosis. Of course, our cells can't
normally be doing all these
things–these draconian measures
need to be initiated only when a
cell is in trouble. Interferon is the
way that cells signal that it's time
to shift into virus-fighting mode.
1rfb
1au1
1itf
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The RCSB PDB is a member of
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(wwPDB; www.wwpdb.org).
References:
S. Bracarda, A. M. M. Eggermont and J. Samuelsson
(2010) Redefining the role of interferon in the treat-
ment of malignant diseases. European Journal of
Cancer 46, 284-297.
R. M. Friedman (2007) Clinical uses of interferons.
British Journal of Clinical Pharmacology 65, 158-162.
Pestka, C. D. Krause and M. R. Walter (2004)
Interferons, interferon-like cytokines, and their recep-
tors. Immunological Reviews 202, 8-32.
1itf:
W. Klaus, B. Gsell, A.M. Labhardt, B. Wipf, H.
Senn (1997) The three-dimensional high resolution
structure of human interferon alpha-2a determined by
heteronuclear NMR spectroscopy in solution.
J.Mol.Biol. 274, 661-675.
1au1:
M. Karpusas, M. Nolte, C.B. Benton, W.
Meier, W.N. Lipscomb, S. Goelz (1997) The crystal
structure of human interferon beta at 2.2-A resolu-
tion. Proc.Natl.Acad.Sci.USA 94, 11813-11818.
1rfb:
C.T. Samudzi, J.R. Rubin (1993) Structure of
recombinant bovine interferon-gamma at 3.0 A reso-
lution. Acta Crystallogr.,Sect.D 49, 513-521.
3bes:
A.A. Nuara, L.J. Walter, N.J. Logsdon, S.I.
Yoon, B.C. Jones, J.M. Schriewer, R.M. Buller, M.R.
Walter (2008) Structure and mechanism of IFN-
gamma antagonism by an orthopoxvirus IFN-
gamma-binding protein. Proc.Natl.Acad.Sci.Usa 105,
1861-1866.
1fg9:
D.J. Thiel, M.H. le Du, R.L. Walter, A. D`Arcy,
C. Chene, M. Fountoulakis, G. Garotta, F.K.
Winkler, S.E. Ealick (2000) Observation of an unex-
pected third receptor molecule in the crystal structure
of human interferon-gamma receptor complex.
Structure Fold.Des. 8, 927-936.
2kz1:
I. Nudelman, S.R. Akabayov, E. Schnur, Z.
Biron, R. Levy, Y. Xu, D. Yang, J. Anglister (2010)
Intermolecular interactions in a 44 kDa interferon-
receptor complex detected by asymmetric reverse-pro-
tonation and two-dimensional NOESY. Biochemistry
49, 5117-5133.
INTERFERONS
Exploring the Structure
As with many other signaling proteins, interfer-
ons bring together two copies of a receptor to
initiate the signal inside the cells. Interferon-
gamma is a dimeric protein, and two copies of its
receptor bind on either side, as seen in PDB entry
1fg9
. Interferon-alpha, on the other hand, is
monomeric, and two different receptor chains
bind to different portions of the protein. PDB
entry
2kz1
shows the interaction with one of the
receptor chains.
Viruses Fight Back
V
iruses are tricky, and as you might expect, they
have evolved many ways to fight the protection
that is elicited by interferons. Different viruses
block different steps in interferon action, all the
way from the binding of interferon to its recep-
tor to the cascade of signals that ultimately
reach the nucleus. For instance, the protein
shown here (PDB entry
3bes
) is from the virus
that causes a smallpox-like disease in mice. It
traps interferon (shown in red) and prevents it
from binding to its receptor.
Topics for Further Exploration
1.Interferon-gamma forms a domain-swapped dimer. You can see this by comparing the folding of
the chain in structures of interferon-alpha and interferon-gamma.
2.The PDB includes several other viral proteins that block interferon action. Can you find them and
determine how they attack the interferon process?
3bes
1fg9
2kz1