Structural basis for selectivity and antagonism in extracellular GPCR-nanobodies. Nat Commun 2024 May 30;15(1):4611
Date
05/31/2024Pubmed ID
38816420Pubmed Central ID
PMC11139983DOI
10.1038/s41467-024-49000-xScopus ID
2-s2.0-85194992751 (requires institutional sign-in at Scopus site) 17 CitationsAbstract
G protein-coupled receptors (GPCRs) are pivotal therapeutic targets, but their complex structure poses challenges for effective drug design. Nanobodies, or single-domain antibodies, have emerged as a promising therapeutic strategy to target GPCRs, offering advantages over traditional small molecules and antibodies. However, an incomplete understanding of the structural features enabling GPCR-nanobody interactions has limited their development. In this study, we investigate VUN701, a nanobody antagonist targeting the atypical chemokine receptor 3 (ACKR3). We determine that an extended CDR3 loop is required for ACKR3 binding. Uncommon in most nanobodies, an extended CDR3 is prevalent in GPCR-targeting nanobodies. Combining experimental and computational approaches, we map an inhibitory ACKR3-VUN701 interface and define a distinct conformational mechanism for GPCR inactivation. Our results provide insights into class A GPCR-nanobody selectivity and suggest a strategy for the development of these new therapeutic tools.
Author List
Schlimgen RR, Peterson FC, Heukers R, Smit MJ, McCorvy JD, Volkman BFAuthors
John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of WisconsinBrian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsHEK293 Cells
Humans
Protein Binding
Receptors, CXCR
Receptors, G-Protein-Coupled
Single-Domain Antibodies
