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J. Biol. Chem., Vol. 282, Issue 20, 15073-15080, May 18, 2007

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Structural Basis for Recognition of CD20 by Therapeutic Antibody Rituximab^*

Jiamu Du, Hao Wang^¶, Chen Zhong, Baozhen Peng, Meilan Zhang, Bohua Li^¶, Sheng Huo^¶, Yajun Guo^¶1, and Jianping Ding²

From the State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Graduate School of Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China and the ^¶International Joint Cancer Institute, Second Military Medical University, 800 Xiang-Yin Road, Shanghai 200433, China

Rituximab is a widely used monoclonal antibody drug for treating certain lymphomas and autoimmune diseases. To understand the molecular mechanism of recognition of human CD20 by Rituximab, we determined the crystal structure of the Rituximab Fab in complex with a synthesized peptide comprising the CD20 epitope (residues 163-187) at 2.6-Å resolution. The combining site of the Fab consists of four complementarity determining regions that form a large, deep pocket to accommodate the epitope peptide. The bound peptide assumes a unique cyclic conformation that is constrained by a disulfide bond and a rigid proline residue (Pro¹⁷²). The ¹⁷⁰ANPS¹⁷³ motif of CD20 is deeply embedded into the pocket on the antibody surface and plays an essential role in the recognition and binding of Rituximab. The antigen-antibody interactions involve both hydrogen bonds and van der Waals contacts and display a high degree of structural and chemical complementarity. These results provide a molecular basis for the specific recognition of CD20 by Rituximab as well as valuable information for development of improved antibody drugs with better specificity and higher affinity.

Received for publication, February 26, 2007 , and in revised form, March 19, 2007.

The atomic coordinates and structure factors (code 2OSL) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by Ministry of Science and Technology of China Grants 2004CB720102, 2004CB720101, 2006CB806501, and 2006AA02Z112 and National Natural Science Foundation of China Grant 30570379. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence may be addressed: 800 Xiang-Yin Rd., Shanghai 200433, China. Tel.: 086-21-2507-0241; Fax: 086-21-2507-4349; E-mail: yjguo{at}smmu.edu.cn. ² To whom correspondence may be addressed: 320 Yue-Yang Rd., Shanghai 200031, China. Tel.: 086-21-5492-1619; Fax: 086-21-5492-1116; E-mail: jpding{at}sibs.ac.cn.

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