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

Tae Yoon Kim; Jeong Seok Cha; Hoyoung Kim; Yoonjoo Choi; Hyun Soo Cho; Hak Sung Kim

doi:10.1016/j.csbj.2021.02.013

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

Tae Yoon Kim, Jeong Seok Cha, Hoyoung Kim, Yoonjoo Choi, Hyun Soo Cho, Hak Sung Kim

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	1325-1334
Number of pages	10
Journal	Computational and Structural Biotechnology Journal
Volume	19
DOIs	https://doi.org/10.1016/j.csbj.2021.02.013
Publication status	Published - 2021 Jan

Bibliographical note

Funding Information:
This research was supported by the Bio & Medical Technology Development Program (NRF-2017M3A9F5031419 to H.-S.K., NRF-2017M3A9F6029755, NRF-2019M3E5D6063903 to H.-S.C), Global Research Laboratory (NRF-2015K1A1A2033346 to H.-S.K.), Mid-Career Researcher Program (NRF-2017R1A2A1A05001091 to H.-S.K.), NRF-2018R1A5A2024181 to Y.j.C., Science Research Center (NRF-2016R1A5A1010764 to H.-S.C) of the National Research Foundation (NRF) funded by the Ministry of Science and ICT of Korea. We thank the staff scientists for assistance at the beamline 1A and 17A of the Photon Factory and the beamline 11C of Pohang Light Source.

Publisher Copyright:
© 2021 The Author(s)

All Science Journal Classification (ASJC) codes

Biotechnology
Biophysics
Structural Biology
Biochemistry
Genetics
Computer Science Applications

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10.1016/j.csbj.2021.02.013

Cite this

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title = "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.",

author = "Kim, {Tae Yoon} and Cha, {Jeong Seok} and Hoyoung Kim and Yoonjoo Choi and Cho, {Hyun Soo} and Kim, {Hak Sung}",

note = "Funding Information: This research was supported by the Bio & Medical Technology Development Program (NRF-2017M3A9F5031419 to H.-S.K., NRF-2017M3A9F6029755, NRF-2019M3E5D6063903 to H.-S.C), Global Research Laboratory (NRF-2015K1A1A2033346 to H.-S.K.), Mid-Career Researcher Program (NRF-2017R1A2A1A05001091 to H.-S.K.), NRF-2018R1A5A2024181 to Y.j.C., Science Research Center (NRF-2016R1A5A1010764 to H.-S.C) of the National Research Foundation (NRF) funded by the Ministry of Science and ICT of Korea. We thank the staff scientists for assistance at the beamline 1A and 17A of the Photon Factory and the beamline 11C of Pohang Light Source. Publisher Copyright: {\textcopyright} 2021 The Author(s)",

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N2 - 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.

AB - 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.

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

Abstract

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