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Science 292 (5522): 1725-1728

Copyright © 2001 by the American Association for the Advancement of Science

Structure of Complement Receptor 2 in Complex with Its C3d Ligand

Gerda Szakonyi,1* Joel M. Guthridge,2* Dawei Li,1 Kendra Young,2 V. Michael Holers,2 Xiaojiang S. Chen1dagger

Complement receptor 2 (CR2/CD21) is an important receptor that amplifies B lymphocyte activation by bridging the innate and adaptive immune systems. CR2 ligands include complement C3d and Epstein-Barr virus glycoprotein 350/220. We describe the x-ray structure of this CR2 domain in complex with C3d at 2.0 angstroms. The structure reveals extensive main chain interactions between C3d and only one short consensus repeat (SCR) of CR2 and substantial SCR side-side packing. These results provide a detailed understanding of receptor-ligand interactions in this protein family and reveal potential target sites for molecular drug design.

1 Department of Biochemistry and Molecular Genetics,
2 Departments of Medicine and Immunology, University of Colorado Health Science Center, School of Medicine, Denver, CO 80262, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: Xiaojiang.Chen{at}

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J. Biol. Chem. 288, 19197-19210
   Abstract »    Full Text »    PDF »
A Crystal Structure of the Complex Between Human Complement Receptor 2 and Its Ligand C3d.
J. M. H. van den Elsen and D. E. Isenman (2011)
Science 332, 608-611
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Mutational Analyses Reveal that the Staphylococcal Immune Evasion Molecule Sbi and Complement Receptor 2 (CR2) Share Overlapping Contact Residues on C3d: Implications for the Controversy Regarding the CR2/C3d Cocrystal Structure.
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J. Immunol. 184, 1946-1955
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Constrained solution scattering modelling of human antibodies and complement proteins reveals novel biological insights.
S. J. Perkins, A. I. Okemefuna, R. Nan, K. Li, and A. Bonner (2009)
J R Soc Interface 6, S679-S696
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Mapping of the C3d Ligand Binding Site on Complement Receptor 2 (CR2/CD21) Using Nuclear Magnetic Resonance and Chemical Shift Analysis.
J. M. Kovacs, J. P. Hannan, E. Z. Eisenmesser, and V. M. Holers (2009)
J. Biol. Chem. 284, 9513-9520
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App1: An Antiphagocytic Protein That Binds to Complement Receptors 3 and 2.
P. Stano, V. Williams, M. Villani, E. S. Cymbalyuk, A. Qureshi, Y. Huang, G. Morace, C. Luberto, S. Tomlinson, and M. Del Poeta (2009)
J. Immunol. 182, 84-91
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Cutting Edge: Members of the Staphylococcus aureus Extracellular Fibrinogen-Binding Protein Family Inhibit the Interaction of C3d with Complement Receptor 2.
D. Ricklin, S. K. Ricklin-Lichtsteiner, M. M. Markiewski, B. V. Geisbrecht, and J. D. Lambris (2008)
J. Immunol. 181, 7463-7467
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Molecular Basis of the Interaction between Complement Receptor Type 2 (CR2/CD21) and Epstein-Barr Virus Glycoprotein gp350.
K. A. Young, A. P. Herbert, P. N. Barlow, V. M. Holers, and J. P. Hannan (2008)
J. Virol. 82, 11217-11227
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Molecular Structure and Expression of Anthropic, Ovine, and Murine Forms of Complement Receptor Type 2.
D. Liu, J.-Y. Zhu, and Z.-X. Niu (2008)
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Isolating the Epstein-Barr Virus gp350/220 Binding Site on Complement Receptor Type 2 (CR2/CD21).
K. A. Young, X. S. Chen, V. M. Holers, and J. P. Hannan (2007)
J. Biol. Chem. 282, 36614-36625
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A structural model reveals energy transduction in dynein.
A. W. R. Serohijos, Y. Chen, F. Ding, T. C. Elston, and N. V. Dokholyan (2006)
PNAS 103, 18540-18545
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Characterization of Human Complement Receptor Type 2 (CR2/CD21) as a Receptor for IFN-{alpha}: A Potential Role in Systemic Lupus Erythematosus.
R. Asokan, J. Hua, K. A. Young, H. J. Gould, J. P. Hannan, D. M. Kraus, G. Szakonyi, G. J. Grundy, X. S. Chen, M. K. Crow, et al. (2006)
J. Immunol. 177, 383-394
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Structure of complement factor H carboxyl-terminus reveals molecular basis of atypical haemolytic uremic syndrome.
T. S. Jokiranta, V.-P. Jaakola, M. J. Lehtinen, M. Parepalo, S. Meri, and A. Goldman (2006)
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Identification of Three gp350/220 Regions Involved in Epstein-Barr Virus Invasion of Host Cells.
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The structure of human CD23 and its interactions with IgE and CD21.
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J. Exp. Med. 202, 751-760
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Epitope-Mapping Studies Define Two Major Neutralization Sites on the Vaccinia Virus Extracellular Enveloped Virus Glycoprotein B5R.
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J. Virol. 79, 6260-6271
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Structure of vaccinia complement protein in complex with heparin and potential implications for complement regulation.
V. K. Ganesh, S. A. Smith, G. J. Kotwal, and K. H. M. Murthy (2004)
PNAS 101, 8924-8929
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The Electrostatic Nature of C3d-Complement Receptor 2 Association.
D. Morikis and J. D. Lambris (2004)
J. Immunol. 172, 7537-7547
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Distinct Sequences in the Cytoplasmic Domain of Complement Receptor 2 Are Involved in Antigen Internalization and Presentation.
D. V. Barrault and A. M. Knight (2004)
J. Immunol. 172, 3509-3517
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Expression and Characterization of the C345C/NTR Domains of Complement Components C3 and C5.
C.-T. Thai and R. T. Ogata (2003)
J. Immunol. 171, 6565-6573
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Complement C3b/C3d and Cell Surface Polyanions Are Recognized by Overlapping Binding Sites on the Most Carboxyl-Terminal Domain of Complement Factor H.
J. Hellwage, T. S. Jokiranta, M. A. Friese, T. U. Wolk, E. Kampen, P. F. Zipfel, and S. Meri (2002)
J. Immunol. 169, 6935-6944
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Expression of Human Complement Receptor Type 2 (CD21) in Mice During Early B Cell Development Results in a Reduction in Mature B Cells and Hypogammaglobulinemia.
K. J. Marchbank, L. Kulik, M. G. Gipson, B. P. Morgan, and V. M. Holers (2002)
J. Immunol. 169, 3526-3535
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Mice Deficient in Complement Receptors 1 and 2 Lack a Tissue Injury-Inducing Subset of the Natural Antibody Repertoire.
S. D. Fleming, T. Shea-Donohue, J. M. Guthridge, L. Kulik, T. J. Waldschmidt, M. G. Gipson, G. C. Tsokos, and V. M. Holers (2002)
J. Immunol. 169, 2126-2133
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The crystal structure of human CD21: Implications for Epstein-Barr virus and C3d binding.
A. E. Prota, D. R. Sage, T. Stehle, and J. D. Fingeroth (2002)
PNAS 99, 10641-10646
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The crystal structure of the zymogen catalytic domain of complement protease C1r reveals that a disruptive mechanical stress is required to trigger activation of the C1 complex.
M. Budayova-Spano, M. Lacroix, N. M. Thielens, G. J. Arlaud, J. C. Fontecilla-Camps, and C. Gaboriaud (2002)
EMBO J. 21, 231-239
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Epitope Mapping Using the X-Ray Crystallographic Structure of Complement Receptor Type 2 (CR2)/CD21: Identification of a Highly Inhibitory Monoclonal Antibody That Directly Recognizes the CR2-C3d Interface.
J. M. Guthridge, K. Young, M. G. Gipson, M.-R. Sarrias, G. Szakonyi, X. S. Chen, A. Malaspina, E. Donoghue, J. A. James, J. D. Lambris, et al. (2001)
J. Immunol. 167, 5758-5766
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