How Distinct Hormones Sculpt a Common Receptor: Ligand-Specific Conformational Pathways of the Insulin Receptor

Abstract

The insulin receptor (IR) is a central regulator of metabolism, integrating hormonal cues to coordinate glucose uptake, lipid metabolism, growth, and survival. While insulin is its canonical ligand, IR also responds to insulin-like growth factors (IGF-I and IGF-II) with lower affinity, a cross-reactivity that is physiologically relevant during development and pathologically important in cancer. Despite extensive research, the molecular basis for how distinct hormones engage the same receptor yet elicit different activation modes remained unresolved. In this study, Yan and colleagues determined the first cryo-electron microscopy (cryo-EM) structures of full-length human IR-A bound to IGF-I, alongside those with insulin and IGF-II, under matched experimental conditions. By capturing multiple ligand-occupancy and conformational states, they revealed that insulin and IGFs drive distinct conformational trajectories through a shared architectural framework, reframing IR activation as a ligand-dependent conformational selection process. Insulin rapidly stabilizes the receptor head region, minimizing conformational heterogeneity and promoting synchronized activation, consistent with its fast, concentration-dependent physiological actions. In contrast, IGF-I and IGF-II induce greater conformational plasticity and a pronounced preference for asymmetric intermediate states, favoring sustained and adaptable engagement suited to long-term growth and differentiation. Site-specific analysis showed that while core residues are shared, insulin forms a denser hydrogen-bond network at site 1, whereas IGFs rely more on secondary sites. These findings provide a structural basis for ligand-specific cooperativity and signaling bias, with implications for understanding metabolic diseases and cancer, and for designing selective IR modulators.

1. Introduction

The insulin receptor (IR) lies at the heart of metabolic regulation, integrating hormonal cues to coordinate glucose uptake, lipid metabolism, growth, and survival [1–3]. While insulin is its canonical ligand, the insulin receptor also responds, albeit with lower affinity, to the insulin-like growth factors IGF-I and IGF-II. This cross-reactivity is physiologically relevant during development and tissue growth, and pathologically important in cancer, where the IR-A isoform and IGF-II signaling are frequently upregulated [4]. Despite decades of biochemical and structural investigation, a central question has remained unresolved: how do distinct hormones engage the same receptor yet elicit different modes of activation and downstream signaling [4,5]?

In this study, Yan and colleagues [6] provide a comprehensive structural answer by determining the first cryo-electron microscopy (cryo-EM) structures of full-length human IR-A bound to IGF-I, alongside those with insulin and IGF-II, under matched experimental conditions. By capturing multiple ligand-occupancy and conformational states for each hormone, the authors show that insulin and IGFs do not simply differ in binding affinity. Instead, they drive distinct conformational trajectories through a shared architectural framework, reframing IR activation as a ligand-dependent conformational selection process rather than a uniform on-off switch [7].