1it9

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spinqualitylabelsall models 1it9, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE OF AN ANTIGEN-BINDING FRAGMENT FROM A HUMANIZED VERSION OF THE ANTI-HUMAN FAS ANTIBODY HFE7A

Overview

Binding of Fas ligand to Fas induces apoptosis. The Fas-Fas ligand system, plays important roles in many biological processes, including the, elimination of autoreactive lymphoid cells. We have previously obtained, the mouse anti-Fas antibody HFE7A (m-HFE7A), which specifically induces, apoptosis in inflammatory cells. In order to apply m-HFE7A for human, therapy, we performed antibody humanization of m-HFE7A by grafting the, mouse complementarity-determining regions (CDRs) to a human antibody. Five, versions of humanized HFE7A (h-HFE7A) demonstrated the same, antigen-binding affinity and same competition-binding activity against Fas, as the chimeric HFE7A. Furthermore, these h-HFE7As induced the same degree, of apoptosis in WR19L12a cells that express human Fas on their surface as, chimeric HFE7A does. To further probe the structural basis for antibody, humanization, we determined the three-dimensional structure of the h-HFE7A, antigen-binding fragment (Fab) by X-ray crystallography and compared it, with the crystal structure of the parent m-HFE7A Fab previously, determined. The main-chain conformation in each h-HFE7A CDR is almost, identical to that in m-HFE7A with root mean square (rms) deviations of, 0.14-0.77 A. However, a significant segmental shift was observed in the, CDR-L1 loop. Together with the high temperature factors of the CDR-L1, residues, both the loops are flexible, suggesting that the CDR-L1 loop, would undergo conformational change upon binding to the antigen. Our, results indicate that the humanization of m-HFE7A succeeded in maintaining, the main-chain conformation as well as the flexibility of the CDR loop.

About this Structure

1IT9 is a Protein complex structure of sequences from Mus musculus and homo sapiens. Full crystallographic information is available from OCA.

Reference

Humanization of the mouse anti-Fas antibody HFE7A and crystal structure of the humanized HFE7A Fab fragment., Haruyama H, Ito S, Miyadai K, Takahashi T, Kawaida R, Takayama T, Hanzawa H, Hata T, Yamaguchi J, Yoshida-Kato H, Ichikawa K, Ohsumi J, Yonehara S, Serizawa N, Biol Pharm Bull. 2002 Dec;25(12):1537-45. PMID:12499636

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