Receptor subtype discrimination using extensive shape complementary designed interfaces

Dang, Luke T.; Miao, Yi; Ha, Andrew; Yuki, Kanako; Park, Keunwan; Janda, Claudia Y.; Jude, Kevin M.; Mohan, Kritika; Ha, Nhi; Vallon, Mario; Yuan, Jenny; Vilches-Moure, José G.; Kuo, Calvin J.; Garcia, K. Christopher; Baker, David

doi:10.1038/s41594-019-0224-z

Title: Receptor subtype discrimination using extensive shape complementary designed interfaces

Journal Article · Mon May 13 00:00:00 EDT 2019 · Nature Structural & Molecular Biology

DOI:https://doi.org/10.1038/s41594-019-0224-z· OSTI ID:1532481

Dang, Luke T. ^[1];

^[2]; Ha, Andrew ^[3]; Yuki, Kanako ^[3]; Park, Keunwan ^[4]; Janda, Claudia Y. ^[5];

^[6]; Mohan, Kritika ^[6]; Ha, Nhi ^[3]; Vallon, Mario ^[3]; Yuan, Jenny ^[3]; Vilches-Moure, José G. ^[7]; Kuo, Calvin J. ^[3]; Garcia, K. Christopher ^[6];

^[1]

Univ. of Washington, Seattle, WA (United States). Dept. of Biochemistry; Univ. of Washington, Seattle, WA (United States). Inst. for Protein Design; Univ. of Washington, Seattle, WA (United States). Howard Hughes Medical Inst.
Stanford Univ., CA (United States). Dept. of Molecular and Cellular Physiology; Stanford Univ., CA (United States). School of Medicine, Dept. of Structural Biology; Stanford Univ., CA (United States). Howard Hughes Medical Inst.
Stanford Univ., CA (United States). Dept. of Medicine, Division of Hematology
Korea Inst. of Science and Technology, Gangneung (China). Systems Biotechnology Research Center
Stanford Univ., CA (United States). Dept. of Molecular and Cellular Physiology; Stanford Univ., CA (United States). School of Medicine, Dept. of Structural Biology; Stanford Univ., CA (United States). Howard Hughes Medical Inst.; Princess Máxima Center for Pediatric Oncology, Utrecht (The Netherlands)
Stanford Univ., CA (United States). Dept. of Molecular and Cellular Physiology; Stanford Univ., CA (United States). School of Medicine, Dept. of Structural Biology; Stanford Univ., CA (United States). Howard Hughes Medical Inst.
Stanford Univ., CA (United States). School of Medicine, Dept. of Comparative Medicine

To discriminate between closely related members of a protein family that differ at a limited number of spatially distant positions is a challenge for drug discovery. Here, we describe a combined computational design and experimental selection approach for generating binders targeting functional sites with large, shape complementary interfaces to read out subtle sequence differences for subtype-specific antagonism. Repeat proteins are computationally docked against a functionally relevant region of the target protein surface that varies in the different subtypes, and the interface sequences are optimized for affinity and specificity first computationally and then experimentally. We used this approach to generate a series of human Frizzled (Fz) subtype-selective antagonists with extensive shape complementary interaction surfaces considerably larger than those of repeat proteins selected from random libraries. In vivo administration revealed that Wnt-dependent pericentral liver gene expression involves multiple Fz subtypes, while maintenance of the intestinal crypt stem cell compartment involves only a limited subset.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-76SF00515; AC02-06CH11357; AC02-05CH11231; 1S10OD012289-01A1; U01DK085527; U19AI116484; R01NS100904; U01CA217851

OSTI ID:: 1532481

Journal Information:: Nature Structural & Molecular Biology, Vol. 26, Issue 6; ISSN 1545-9993

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 19 works

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