Reports

Crystal Structure of a Shark Single-Domain Antibody V Region in Complex with Lysozyme

Robyn L. Stanfield,^1* Helen Dooley,^3* Martin F. Flajnik,³ Ian A. Wilson^1,2

Cartilaginous fish are the phylogenetically oldest living organisms known to possess components of the vertebrate adaptive immune system. Key to their immune response are heavy-chain, homodimeric immunoglobulins called new antigen receptors (IgNARs), in which the variable (V) domains recognize antigens with only a single immunoglobulin domain, akin to camelid heavy-chain V domains. The 1.45 angstrom resolution crystal structure of the type I IgNAR V domain in complex with hen egg-white lysozyme (HEL) reveals a minimal antigen-binding domain that contains only two of the three conventional complementarity-determining regions but still binds HEL with nanomolar affinity by means of a binding interface comparable in size to conventional antibodies.

¹ Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
² Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
³ Department of Microbiology and Immunology, University of Maryland at Baltimore, Baltimore, MD 21201–1559, USA, and the National Aquarium in Baltimore, 501 E. Pratt Street, Baltimore, MD 21202, USA.

Note added in proof: While this paper was in production, a paper reporting the structures of the two unliganded type 2 IgNAR variable domains was published (42).

^* These authors contributed equally to this work.

To whom correspondence should be addressed. E-mail: wilson{at}scripps.edu

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High-affinity lamprey VLRA and VLRB monoclonal antibodies.

S. Tasumi, C. A. Velikovsky, G. Xu, S. A. Gai, K. D. Wittrup, M. F. Flajnik, R. A. Mariuzza, and Z. Pancer (2009)
PNAS 106, 12891-12896
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Engineered Human Antibody Constant Domains with Increased Stability.

R. Gong, B. K. Vu, Y. Feng, D. A. Prieto, M. A. Dyba, J. D. Walsh, P. Prabakaran, T. D. Veenstra, S. G. Tarasov, R. Ishima, et al. (2009)
J. Biol. Chem. 284, 14203-14210
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Aggregation-resistant VHs selected by in vitro evolution tend to have disulfide-bonded loops and acidic isoelectric points.

M. Arbabi-Ghahroudi, R. To, N. Gaudette, T. Hirama, W. Ding, R. MacKenzie, and J. Tanha (2009)
Protein Eng. Des. Sel. 22, 59-66
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Single Variable Domain-IgG Fusion: A NOVEL RECOMBINANT APPROACH TO Fc DOMAIN-CONTAINING BISPECIFIC ANTIBODIES.

J. Shen, M. D. Vil, X. Jimenez, M. Iacolina, H. Zhang, and Z. Zhu (2006)
J. Biol. Chem. 281, 10706-10714
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An evolutionarily mobile antigen receptor variable region gene: Doubly rearranging NAR-TcR genes in sharks.

M. F. Criscitiello, M. Saltis, and M. F. Flajnik (2006)
PNAS 103, 5036-5041
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Molecular basis for the preferential cleft recognition by dromedary heavy-chain antibodies.

E. De Genst, K. Silence, K. Decanniere, K. Conrath, R. Loris, J. Kinne, S. Muyldermans, and L. Wyns (2006)
PNAS 103, 4586-4591
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First molecular and biochemical analysis of in vivo affinity maturation in an ectothermic vertebrate.

H. Dooley, R. L. Stanfield, R. A. Brady, and M. F. Flajnik (2006)
PNAS 103, 1846-1851
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Structure of a {gamma}{delta} T Cell Receptor in Complex with the Nonclassical MHC T22.

E. J. Adams, Y.-H. Chien, and K. C. Garcia (2005)
Science 308, 227-231
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