Structures of Adnectin/Protein Complexes Reveal an Expanded Binding Footprint

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• 作者：Vidhyashankar Ramamurthy¹ ; Stanley  ; R. Krystek Jr.¹ ; Alexander Bush² ; Anzhi Wei¹ ; Stuart  ; L. Emanuel¹ ; Ruchira Das  ; Gupta² ; Ahsen Janjua¹ ; Lin Cheng¹ ; Melissa Murdock¹ ; Bozena Abramczyk¹ ; Daniel Cohen¹ ; Zheng Lin¹ ; Paul Morin¹ ; Jonathan  ; H. Davis² ; Michael Dabritz² ; Douglas  ; C. McLaughlin² ; Katie  ; A. Russo² ; Ginger Chao² ; Martin  ; C. Wright² ; Victoria  ; A. Jenny² ; Linda  ; J. Engle² ; Eric Furfine² ; Steven Sheriff¹ ; ^{steven.sheriff@bms.com}
• 刊名：Structure
• 出版年：2012
• 出版时间：8 February 2012
• 年：2012
• 卷：20
• 期：2
• 页码：259-269
• 全文大小：1283 K

文摘

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Summary

Adnectins are targeted biologics derived from the tenth type III domain of human fibronectin (¹⁰Fn3), a member of the immunoglobulin superfamily. Target-specific binders are selected from libraries generated by diversifying the three ¹⁰Fn3 loops that are analogous to the complementarity determining regions of antibodies. The crystal structures of two Adnectins were determined, each in complex with its therapeutic target, EGFR or IL-23. Both Adnectins bind different epitopes than those bound by known monoclonal antibodies. Molecular modeling suggests that some of these epitopes might not be accessible to antibodies because of the size and concave shape of the antibody combining site. In addition to interactions from the Adnectin diversified loops, residues from the N terminus and/or the ¦Â strands interact with the target proteins in both complexes. Alanine-scanning mutagenesis confirmed the calculated binding energies of these ¦Â strand interactions, indicating that these nonloop residues can expand the available binding footprint.