Importance of integrin transmembrane helical interactions for antagonistic versus agonistic ligand behavior: Consequences for medical applications

Ute Reuning; Vincenzo Maria D'Amore; Kairbaan Hodivala-Dilke; Luciana Marinelli; Horst Kessler

doi:10.1016/j.bioorg.2025.108193

Importance of integrin transmembrane helical interactions for antagonistic versus agonistic ligand behavior: Consequences for medical applications

Bioorg Chem. 2025 Jan 19:156:108193. doi: 10.1016/j.bioorg.2025.108193. Online ahead of print.

Authors

Ute Reuning¹, Vincenzo Maria D'Amore², Kairbaan Hodivala-Dilke³, Luciana Marinelli⁴, Horst Kessler⁵

Affiliations

¹ TUM University Hospital, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Department of Gynecology and Obstetrics, Clinical Research Unit, Ismaninger Strasse 22, 81675 Munich, Germany. Electronic address: [email protected].
² University of Naples Federico II, UNINA-Department of Pharmacy, C.so Umberto I, 40, 80138 Naples, Italy. Electronic address: [email protected].
³ Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom. Electronic address: [email protected].
⁴ University of Naples Federico II, UNINA-Department of Pharmacy, C.so Umberto I, 40, 80138 Naples, Italy. Electronic address: [email protected].
⁵ Institute for Advanced Study, Department of Chemistry, School of Natural Sciences and Bavarian NMR Center (BNMRZ), Technical University Munich, Ernst-Otto-Fischer-Str. 2, 85748 Garching, Germany. Electronic address: [email protected].

PMID: 39842299
DOI: 10.1016/j.bioorg.2025.108193

Abstract

Integrins are well-characterized receptors involved in cell adhesion and signaling. With six approved drugs, they are recognized as valuable therapeutic targets. Here, we explore potential activation mechanisms that may clarify the agonist versus antagonist behavior of integrin ligands. The reorganization of the transmembrane domain (TMD) in the integrin receptor, forming homooligomers within focal adhesions, could be key to the understanding of the agonistic properties of integrin ligands at substoichiometric concentrations. This has significant implications for medical applications. While we focus on the RGD peptide-recognizing integrin subfamily, we propose that these mechanistic insights may also apply to other integrin subtypes. For application of integrin ligands in medicine it is essential to consider this mechanism and its consequences for affinity and bioavailability.

Keywords: Agonist; Antagonist; Dose-dependent functional switch; Focal adhesions; Integrin conformational activation and signaling; Integrin ligands; Integrins; Transmembrane domains.

Publication types

Review