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 journalArticlepeer-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 languageEnglish
Article number338
JournalCommunications Biology
Volume2
Issue number1
DOIs
StatePublished - 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.

ASJC Scopus subject areas

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

Fingerprint

Dive into the research topics of 'Development of R7BP inhibitors through cross-linking coupled mass spectrometry and integrated modeling'. Together they form a unique fingerprint.

Cite this