Molecular basis of recognition of human osteopontin by 23C3, a potential therapeutic antibody for treatment of rheumatoid arthritis

	Molecular basis of recognition of human osteopontin by 23C3, a potential therapeutic antibody for treatment of rheumatoid arthritis
	Du, JM; Hou, S; Zhong, C; Lai, Z; Yang, H; Dai, JX; Zhang, DP; Wang, H; Guo, YJ; Ding, JP
刊名	JOURNAL OF MOLECULAR BIOLOGY
	2008
卷号	382 期号:4 页码:835-842
关键词	osteopontin rheumatoid arthritis 23C3 epitope antibody structure
通讯作者	Guo, YJ (reprint author), Second Mil Med Univ, Int Joint Canc Inst, 800 Xiang Yin Rd, Shanghai 200433, Peoples R China.,yjguo@smmu.edu.cn
英文摘要	Osteopontin plays an important role in the development and perpetuation of rheumatoid arthritis (RA). Antibodies targeting osteopontin have shown promising therapeutic benefits against this disease. We have previously reported a novel anti-RA monoclonal antibody, namely, 23C3, and shown it capable of alleviating the symptoms of RA in a murine collagen-induced arthritis model, restoring the cytokine production profile in joint tissues, and reducing T-cell recall responses to collagen type II. We describe here the crystal structure of 23C3 in complex with its epitope peptide. Analyses of the complex structure reveal the molecular mechanism of osteopontin recognition by 23C3. The peptide folds into two tandem beta-turns, and two key residues of the peptide are identified to be critical for the recognition by 23C3: TrpP43 is deeply embedded into a hydrophobic pocket formed by AlaL34, TyrL36, LeuL46, TyrL49, PheL91, and MetH102 and therefore has extensive hydrophobic interactions with 23C3, while AspP47 has a network of hydrophilic interactions with residues ArgH50, ArgH52, SerH53, and AsnH56 of the antibody. Besides the complementarity-determining region loops, the framework region L2 of 230 is also shown to interact with the epitope peptide, which is not common in the antibody-antigen interactions and thus could be exploited in the engineering of 23C3. These results not only provide valuable information for further improvement of 23C3 such as chimerization or humanization for its therapeutic application, but also reveal the features of this specific epitope of osteopontin that may be useful for the development of new antibody drugs against RA. (C) 2008 Elsevier Ltd. All rights reserved.
学科主题	Biochemistry & Molecular Biology
类目[WOS]	Biochemistry & Molecular Biology
关键词[WOS]	COLLAGEN-INDUCED ARTHRITIS ; MONOCLONAL-ANTIBODY ; PROTEIN ; PEPTIDE ; ANTIGEN ; INTEGRINS ; BINDING ; METHOTREXATE ; CHEMOTAXIS ; APOPTOSIS
收录类别	SCI
语种	英语
WOS记录号	WOS:000260024500002
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/1363]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Du, JM,Hou, S,Zhong, C,et al. Molecular basis of recognition of human osteopontin by 23C3, a potential therapeutic antibody for treatment of rheumatoid arthritis[J]. JOURNAL OF MOLECULAR BIOLOGY,2008,382(4):835-842.
APA	Du, JM.,Hou, S.,Zhong, C.,Lai, Z.,Yang, H.,...&Ding, JP.(2008).Molecular basis of recognition of human osteopontin by 23C3, a potential therapeutic antibody for treatment of rheumatoid arthritis.JOURNAL OF MOLECULAR BIOLOGY,382(4),835-842.
MLA	Du, JM,et al."Molecular basis of recognition of human osteopontin by 23C3, a potential therapeutic antibody for treatment of rheumatoid arthritis".JOURNAL OF MOLECULAR BIOLOGY 382.4(2008):835-842.