Structural basis for selectivity and antagonism in extracellular GPCR-nanobodies

Roman R. Schlimgen, Francis C. Peterson, Raimond Heukers, Martine J. Smit, John D. McCorvy and Brian F. Volkman ()
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Roman R. Schlimgen: Medical College of Wisconsin
Francis C. Peterson: Medical College of Wisconsin
Raimond Heukers: Vrije Universiteit
Martine J. Smit: Vrije Universiteit
John D. McCorvy: Neurobiology, and Anatomy, Medical College of Wisconsin
Brian F. Volkman: Medical College of Wisconsin

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-49000-x

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