8UEK

Solution structure of ACKR3-targeting nanobody VUN701

Summary for 8UEK

• Entry DOI: 10.2210/pdb8uek/pdb
• NMR Information: BMRB: 31108
• Descriptor: ACKR3-targeting nanobody VUN701 (1 entity in total)
• Functional Keywords: ackr3, gpcr, nanobody, vun701, immune system
• Biological source: Lama glama (llama)
• Total number of polymer chains: 1
• Total formula weight: 13318.54

Authors

Schlimgen, R.R.,Peterson, F.C.,Volkman, B.F. (deposition date: 2023-10-01, release date: 2024-06-12, Last modification date: 2024-11-13)

Primary citation

Schlimgen, R.R.,Peterson, F.C.,Heukers, R.,Smit, M.J.,McCorvy, J.D.,Volkman, B.F.
Structural basis for selectivity and antagonism in extracellular GPCR-nanobodies.
Nat Commun, 15:4611-4611, 2024

PubMed 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.

PubMed: 38816420
DOI: 10.1038/s41467-024-49000-x

Experimental method

SOLUTION NMR