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Computationally-guided design and affinity improvement of a protein binder targeting a specific site on HER2.


ABSTRACT: A protein binder with a desired epitope and binding affinity is critical to the development of therapeutic agents. Here we present computationally-guided design and affinity improvement of a protein binder recognizing a specific site on domain IV of human epidermal growth factor receptor 2 (HER2). As a model, a protein scaffold composed of Leucine-rich repeat (LRR) modules was used. We designed protein binders which appear to bind a target site on domain IV using a computational method. Top 10 designs were expressed and tested with binding assays, and a lead with a low micro-molar binding affinity was selected. Binding affinity of the selected lead was further increased by two-orders of magnitude through mutual feedback between computational and experimental methods. The utility and potential of our approach was demonstrated by determining the binding interface of the developed protein binder through its crystal structure in complex with the HER2 domain IV.

SUBMITTER: Kim TY 

PROVIDER: S-EPMC7941009 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Computationally-guided design and affinity improvement of a protein binder targeting a specific site on HER2.

Kim Tae Yoon TY   Cha Jeong Seok JS   Kim Hoyoung H   Choi Yoonjoo Y   Cho Hyun-Soo HS   Kim Hak-Sung HS  

Computational and structural biotechnology journal 20210227


A protein binder with a desired epitope and binding affinity is critical to the development of therapeutic agents. Here we present computationally-guided design and affinity improvement of a protein binder recognizing a specific site on domain IV of human epidermal growth factor receptor 2 (HER2). As a model, a protein scaffold composed of Leucine-rich repeat (LRR) modules was used. We designed protein binders which appear to bind a target site on domain IV using a computational method. Top 10 d  ...[more]

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