Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain

Glucose homeostasis and growth essentially depend on the hormone insulin engaging its receptor. Despite biochemical and structural advances, a fundamental contradiction has persisted in the current understanding of insulin ligand-receptor interactions. While biochemistry predicts two distinct insulin binding sites, 1 and 2, recent structural analyses have resolved only site 1. Using a combined approach of cryo-EM and atomistic molecular dynamics simulation, we present the structure of the entire dimeric insulin receptor ectodomain saturated with four insulin molecules. Complementing the previously described insulin-site 1 interaction, we present the first view of insulin bound to the discrete insulin receptor site 2. Insulin binding stabilizes the receptor ectodomain in a T-shaped conformation wherein the membrane-proximal domains converge and contact each other. These findings expand the current models of insulin binding to its receptor and of its regulation. In summary, we provide the structural basis for a comprehensive description of ligand-receptor interactions that ultimately will inform new approaches to structure-based drug design.Peer reviewe

A Comparative Structural Bioinformatics Analysis of the Insulin Receptor Family Ectodomain Based on Phylogenetic Information

The insulin receptor (IR), the insulin-like growth factor 1 receptor (IGF1R) and the insulin receptor-related receptor (IRR) are covalently-linked homodimers made up of several structural domains. The molecular mechanism of ligand binding to the ectodomain of these receptors and the resulting activation of their tyrosine kinase domain is still not well understood. We have carried out an amino acid residue conservation analysis in order to reconstruct the phylogeny of the IR Family. We have confirmed the location of ligand binding site 1 of the IGF1R and IR. Importantly, we have also predicted the likely location of the insulin binding site 2 on the surface of the fibronectin type III domains of the IR. An evolutionary conserved surface on the second leucine-rich domain that may interact with the ligand could not be detected. We suggest a possible mechanical trigger of the activation of the IR that involves a slight ‘twist’ rotation of the last two fibronectin type III domains in order to face the likely location of insulin. Finally, a strong selective pressure was found amongst the IRR orthologous sequences, suggesting that this orphan receptor has a yet unknown physiological role which may be conserved from amphibians to mammals

Assessing human diet and movement in the Tongan maritime chiefdom using isotopic analyses.

The rise of stratified societies fundamentally influences the interactions between status, movement, and food. Using isotopic analyses, we assess differences in diet and mobility of individuals excavated from two burial mounds located at the `Atele burial site on Tongatapu, the main island of the Kingdom of Tonga (c. 500 - 150 BP). The first burial mound (To-At-1) was classified by some archaeologists as a commoner's mound while the second burial mound (To-At-2) was possibly used for interment of the chiefly class. In this study, stable isotope analyses of diet (δ13C, δ15N, and δ34S; n = 41) are used to asses paleodiet and 87Sr/86Sr ratios (n = 30) are analyzed to investigate individual mobility to test whether sex and social status affected these aspects of life. Our results show significant differences in diet between burial mounds and sexes. Those interred in To-At-2 displayed lower δ13C values, indicating they ate relatively more terrestrial plants (likely starchy vegetable staples) compared with To-At-1 individuals. Females displayed significantly lower δ15N values compared with males within the entire assemblage. No differences in δ34S values were observed between sexes or burial mound but it is possible that sea spray or volcanism may have affected these values. One individual displayed the strontium isotopic composition representative of a nonlocal immigrant (outside 2SD of the mean). This suggests the hegemonic control over interisland travel, may have prevented long-term access to the island by non-Tongans exemplifying the political and spiritual importance of the island of Tongatapu in the maritime chiefdom

Beyond catch-up: could China become the global innovation powerhouse? China’s innovation progress and challenges from a holistic innovation perspective

Abstract Over the past century and a half, global technological leadership has shifted from Europe to the United States, while scholars argue that the world has seen that it is now shifting from the United States to China due to China’s extraordinary catch-up in the past four decades, in which the public policy-oriented national innovation system development plays a critical role that might provide an alternative way for innovation-driven development especially for emerging markets. Even though encountering many challenges ahead, China is positioning itself to take over the global innovation leadership in the next few decades. Here in this article, we introduce a serious yet underexplored question: could China go beyond catch-up and become the global innovation powerhouse? Specifically, drawing from the holistic innovation perspective, which is an original theoretical paradigm for the mission-oriented innovation policy change, this article critically reviews, both qualitatively and quantitatively, China’s remarkable innovation progress and main drivers in comparison with G7 countries plus South Korea and India, trying to provide a comprehensive and critical view of state-of-the-art research on China’s innovation catch-up. We further explore the five major challenges that China must take seriously when marching toward the global innovation powerhouse. Finally, we propose a mission-oriented holistic STI policy design framework for both China and other emerging economies to go beyond catch-up in a competitive dynamic world. This article provides a new and holistic perspective to access China’s innovation progress and challenges, also generates novel insights for scholars and public agencies to contribute to global innovation development, with a shared goal of achieving global sustainable development in the post-COVID-19 pandemic world.</jats:p

Bending at Thy Throne: For Unison or SATB Choir and Organ

Text by William Jervois (1852-1905) and W.B. Trevelyan (1853-1929) ; music by Brett McKern, op. 117. Duration: 3'30". "May be sung in SATB harmony or as a unison anthem, all voices singing the soprano part"--Page [1]