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Laboratory of Molecular Biophysics
Laboratory Journal 2004
Susan Lea
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Susan Lea
Structural Studies of Host-Pathogen Interactions
Postdoctoral associates: Dr. Pietro
Roversi, Dr. Stephen Johnson
Graduate students: Rachel Abbott, Frank Cordes, David
Pettigrew
Disease resulting from infection of a host by any organism, be it
viral, bacterial or fungal, must, a priori, involve formation
of complexes between proteins derived from the invading organism and
the host. We are using a variety of methods to look at the constraints
that formation of these complexes places on the evolution of both the
pathogenic agent and the host and, in the long-term, hope to exploit
structural information about such complexes to develop therapeutic
agents.
This year we have determined novel structures for several pathogen and
host derived proteins. A long-standing interest in the essential
interactions between viruses and their receptor molecules (e.g. Lea
& Stuart 1995, Lea et al 1998 & Fry et al 1999) has this year
been focused on studies of Echoviruses 11 and 12 (EV11, EV12), human
picornaviruses. Most infections with these viruses are
symptomless but in neonates, and occasionally in adults, infection with
EV11 can lead to meningitis and cardiac myopathies. In collaboration
with David Brown and others at the University of Cambridge we have
solved the structure of an EV11 derived from a clinical sample at
2.9Å (Stuart et al 2002). This EV11 uses Decay Accelerating
Factor (DAF, CD55) as a receptor and the structure provides a framework
for understanding of a series of mutant viruses which demonstrate that
simple changes in the amino acid composition of the coat proteins allow
this virus to become independent of CD55 in its infection process. Our
recent structure of its receptor, the complement regulator CD55
(Lukacik et al 2004) and of CD55 in complex with EV12 (Bhella et al
2004) have begun to extend our understanding of many aspects of this
multifaceted protein.
More recently we have begun to study bacterial systems relevant to
pathogenesis with atomic structures solved this year for two bacterial
adhesions (Anderson et al, 2004 & Pettigrew et al 2004), for a
Borrelial protein critical for the chronic forms of the disease (Cordes
et al, submitted) and a low resolution structure for the Shigella
needle (Cordes et al 2003). This work has moved forward rapidly with
our collaboration with Dr. A. Blocker leading to the first structural
evidence of multiple helical states for the needle being linked to the
functional state of the needle (Cordes et al, submitted) and with the
production of crystals for the needle subunit and for one of the
components of the translocon.
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Figure: Structures solved in 2003-2004
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References
Pettigrew, D., Anderson, K.L., Billington, J., Cota, E., Simpson, P.,
Urvil, P., Rabuzin, F., Roversi, P., Nowicki, B., du Merle, L., Le
Bouguenec, C., Matthews, S. & Lea, S.M. (2004) High resolution
studies of the Afa/Dr adhesin DraE and its interaction with
chloramphenicol. J. Biol. Chem. 279, 46851-46857
Anderson, K.L., Billington, J., Pettigrew, D., Cota, E., Simpson, P.,
Roversi, P., Chen, H.A., Urvil, P., du Merle, L., Barlow, P.N., Medof,
M.E., Smith, R.A.G., Nowicki, B., Le Bouguenec, C., Lea, S.M.
& Matthews, S. (2004) An Atomic Resolution Model for Assembly,
Architecture, and Function of the Dr Adhesins Molecular Cell 15, 647-657
White, J., Lukacik, P., Esser, D., Steward, M., Giddings, N., Bright,
J., Fritchley, S.J., Morgan, B.P., Lea, S.M., Smith, G.P. &
Smith, R.A.G. (2004) Biological activity, membrane-targeting
modification and crystallization of soluble human decay accelerating
factor expressed in E.coli. Protein Science 13, 2406-2415
Blanc, E., Roversi, P., Vornhein, C., Flensburg, C., Lea, S.M. &
Bricogne, G. (2004) Refinement of severely incomplete structures with
maximum likelihood in Buster-TNT. Acta Cryst. D60, 2210-2221
Abbott, R., Knott, V., Roversi, P., Neudeck, S., Handford, P.A. &
Lea, S.M. (2004) Crystallisation and preliminary X-ray diffraction
analysis of three EGF domains of EMR2, a 7-TM immune system molecule.
Acta Cryst. D 60, 936-938
Cordes, F.S., Kraiczy, P., Roversi, P., Jahraus, O., Simon, M., Skerka,
C., Kirschfink, M., Brade, V., Lowe, E., Zipfel, P., Wallich, R. &
Lea, S.M. (2004) Crystallisation and preliminary crystallographic
analysis of BbCRASP-1, a complement regulator-acquiring surface protein
of Borrelia burgdorferi. Acta Cryst. D 60, 929-932
Williams, D.T., Chaudhry, Y., Goodfellow, I., Lea, S.M. &
Evans, D. (2004) Interaction of Decay Accelerating Factor (DAF) with
hemagluttinating human enteroviruses: Utilising variation in primate
DAF to map virus binding sites. J. Gen. Virol. 85, 731-738
Bhella, D., Goodfellow, I., Roversi, P., Pettigrew, D., Chaudhry, Y.,
Evans, D.J. & Lea, S.M. (2004) The structure of echovirus type 12
bound to a two-domain fragment of its cellular attachment protein
decay-accelerating factor (CD55) J. Biol. Chem. 279, 8325-8332
Lukacik, P., Roversi, P. , White, J., Esser, D., Smith G.P.,
Billington, J., Williams, P., Rudd, P.M., Wormald, M.R., Crispin,
M.D.M., Radcliffe, C.M., Dwek, R.A. , Evans, D.J., Morgan, B.P., Smith,
R.A.G. & Lea, S.M. (2004) Complement regulation at the molecular
level: the structure of Decay Accelerating Factor. Proc. Natl.
Acad. Sci. USA 101, 1279-1284
Gallego, J., Greatorex, J., Zhang, H., Yang, B., Arunachalam, S., Fang,
J., Lea, S.M., Pomerantz, R.J. & Lever, A.M.L. (2003) Rev binds
specifically to a purine loop in the SL1 region of the HIV-1 leader
RNA. J. Biol. Chem. 278, 40385-40391
Kriegshauser, G., Wutz, G., Lea, S.M., Stuart, D., Skern, T. &
Kuechler, E. (2003) Model of Equine Rhinitis-A virus Capsid:
Identification of a Major Neutralizing Immunogenic Site J. Gen. Virol
84, 2365-2373
Cordes, F.S., Komoriya, K., Larquet, E., Yang, S., Egelman, E.,
Blocker, A. & Lea, S.M. (2003) Helical Structure of the Needle of
the Type III Secretion System of Shigella Flexneri J. Biol. Chem. 278,
17103-7.
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Last updated: 26-APR-2005 16:05