Development of R7BP inhibitors through cross-linking coupled mass spectrometry and integrated modeling

Poorni R. Adikaram; Jian Hua Zhang; Claire M. Kittock; Mritunjay Pandey; Sergio A. Hassan; Nicole G. Lue; Guanghui Wang; Marjan Gucek; William F. Simonds

doi:10.1038/s42003-019-0585-1

Development of R7BP inhibitors through cross-linking coupled mass spectrometry and integrated modeling

Poorni R. Adikaram, Jian Hua Zhang, Claire M. Kittock, Mritunjay Pandey, Sergio A. Hassan, Nicole G. Lue, Guanghui Wang, Marjan Gucek, William F. Simonds

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

4 Scopus citations

Abstract

Protein-protein interaction (PPI) networks are known to be valuable targets for therapeutic intervention; yet the development of PPI modulators as next-generation drugs to target specific vertices, edges, and hubs has been impeded by the lack of structural information of many of the proteins and complexes involved. Building on recent advancements in cross-linking mass spectrometry (XL-MS), we describe an effective approach to obtain relevant structural data on R7BP, a master regulator of itch sensation, and its interfaces with other proteins in its network. This approach integrates XL-MS with a variety of modeling techniques to successfully develop antibody inhibitors of the R7BP and RGS7/Gβ5 duplex interaction. Binding and inhibitory efficiency are studied by surface plasmon resonance spectroscopy and through an R7BP-derived dominant negative construct. This approach may have broader applications as a tool to facilitate the development of PPI modulators in the absence of crystal structures or when structural information is limited.

Original language	English
Article number	338
Journal	Communications Biology
Volume	2
Issue number	1
DOIs	https://doi.org/10.1038/s42003-019-0585-1
State	Published - Dec 1 2019

Bibliographical note

Publisher Copyright:
© 2019, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Funding

The authors thank the members of the Metabolic Diseases Branch, NIDDK for many helpful discussions and suggestions. The authors also thank Dr. Yong Chen from the NHLBI Proteomics Core for help with sample processing and data analysis. The Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (ZIA DK043304-24) supported this research.

Funders	Funder number
National Institute of Diabetes and Digestive and Kidney Diseases	ZIADK043304

ASJC Scopus subject areas

Medicine (miscellaneous)
General Biochemistry, Genetics and Molecular Biology
General Agricultural and Biological Sciences

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10.1038/s42003-019-0585-1

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abstract = "Protein-protein interaction (PPI) networks are known to be valuable targets for therapeutic intervention; yet the development of PPI modulators as next-generation drugs to target specific vertices, edges, and hubs has been impeded by the lack of structural information of many of the proteins and complexes involved. Building on recent advancements in cross-linking mass spectrometry (XL-MS), we describe an effective approach to obtain relevant structural data on R7BP, a master regulator of itch sensation, and its interfaces with other proteins in its network. This approach integrates XL-MS with a variety of modeling techniques to successfully develop antibody inhibitors of the R7BP and RGS7/Gβ5 duplex interaction. Binding and inhibitory efficiency are studied by surface plasmon resonance spectroscopy and through an R7BP-derived dominant negative construct. This approach may have broader applications as a tool to facilitate the development of PPI modulators in the absence of crystal structures or when structural information is limited.",

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AU - Zhang, Jian Hua

AU - Kittock, Claire M.

AU - Pandey, Mritunjay

AU - Hassan, Sergio A.

AU - Lue, Nicole G.

AU - Wang, Guanghui

AU - Gucek, Marjan

AU - Simonds, William F.

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AB - Protein-protein interaction (PPI) networks are known to be valuable targets for therapeutic intervention; yet the development of PPI modulators as next-generation drugs to target specific vertices, edges, and hubs has been impeded by the lack of structural information of many of the proteins and complexes involved. Building on recent advancements in cross-linking mass spectrometry (XL-MS), we describe an effective approach to obtain relevant structural data on R7BP, a master regulator of itch sensation, and its interfaces with other proteins in its network. This approach integrates XL-MS with a variety of modeling techniques to successfully develop antibody inhibitors of the R7BP and RGS7/Gβ5 duplex interaction. Binding and inhibitory efficiency are studied by surface plasmon resonance spectroscopy and through an R7BP-derived dominant negative construct. This approach may have broader applications as a tool to facilitate the development of PPI modulators in the absence of crystal structures or when structural information is limited.

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Development of R7BP inhibitors through cross-linking coupled mass spectrometry and integrated modeling

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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