Structural basis for selectivity and antagonism in extracellular GPCR-nanobodies

Roman R. Schlimgen; Francis C. Peterson; Raimond Heukers; Martine J. Smit; John D. McCorvy; Brian F. Volkman

doi:10.1038/s41467-024-49000-x

Structural basis for selectivity and antagonism in extracellular GPCR-nanobodies

Roman R. Schlimgen, Francis C. Peterson, Raimond Heukers, Martine J. Smit, John D. McCorvy, Brian F. Volkman^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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.

Original language	English
Article number	4611
Pages (from-to)	1-10
Number of pages	10
Journal	Nature Communications
Volume	15
Early online date	30 May 2024
DOIs	https://doi.org/10.1038/s41467-024-49000-x
Publication status	Published - 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

We thank Shawn Jenjak, Dr. Andrew Kleist, and Dr. Acacia Dishman for their comments on the manuscript figures and Julian Grosskopf for his assistance in optimizing the efficiency of the molecular dynamics simulations. This research was completed in part with computational resources and technical support provided by the Research Computing Center at the Medical College of Wisconsin. This work was supported by a National Institutes of Health Allergy and Infectious Disease grant (NIAID R37AI058072 to B.F.V.), by a National Institutes of Health General Medical Sciences grant (NIGMS R35GM133421 to J.D.M.), and by the European Union H2020-MSCA Program (Grant agreement 860229-ONCORNET2.0 for R.H. and M.J.S.

Funders	Funder number
Shawn Jenjak
National Institute of Allergy and Infectious Diseases	R37AI058072
National Institute of Allergy and Infectious Diseases
National Institute of General Medical Sciences	R35GM133421
National Institute of General Medical Sciences
European Union H2020-MSCA Program	860229-ONCORNET2.0

Access to Document

10.1038/s41467-024-49000-x

Persistent URL (handle)

Persistent link

Cite this

@article{9ff5e4ed408447bcbe43a4b419c8f037,

title = "Structural basis for selectivity and antagonism in extracellular GPCR-nanobodies",

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.",

author = "Schlimgen, {Roman R.} and Peterson, {Francis C.} and Raimond Heukers and Smit, {Martine J.} and McCorvy, {John D.} and Volkman, {Brian F.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

doi = "10.1038/s41467-024-49000-x",

language = "English",

volume = "15",

pages = "1--10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Structural basis for selectivity and antagonism in extracellular GPCR-nanobodies

AU - Schlimgen, Roman R.

AU - Peterson, Francis C.

AU - Heukers, Raimond

AU - Smit, Martine J.

AU - McCorvy, John D.

AU - Volkman, Brian F.

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85194992751&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85194992751&partnerID=8YFLogxK

U2 - 10.1038/s41467-024-49000-x

DO - 10.1038/s41467-024-49000-x

M3 - Article

C2 - 38816420

AN - SCOPUS:85194992751

SN - 2041-1723

VL - 15

SP - 1

EP - 10

JO - Nature Communications

JF - Nature Communications

M1 - 4611

ER -

Structural basis for selectivity and antagonism in extracellular GPCR-nanobodies

Abstract

Bibliographical note

Funding

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this