Insulin receptor Arg717 and IGF-1 receptor Arg704 play a key role in ligand binding and in receptor activation

Kertisová, Anna; Žáková, Lenka; Macháčková, Kateřina; Marek, Aleš; Šácha, Pavel; Pompach, Petr; Jiráček, Jiří; Selicharová, Irena

doi:10.1098/rsob.230142

Cited by 7 publications

(3 citation statements)

References 50 publications

(168 reference statements)

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“…Any substitution of this residue with different amino acids results in inactivation, and this interaction was captured through molecular dynamics (MD) simulations. 84 Overall, these simulations provided us with a global understanding of the patterns of recognition of human insulin at the IR.…”

Section: Discussionmentioning

confidence: 95%

Mapping Structural Drivers of Insulin Analogs Using Molecular Dynamics and Free Energy Calculations at Insulin Receptor

Sena

Gromiha

Chatterji

et al. 2022

Preprint

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Insulin has been the cornerstone of diabetes treatment since its discovery over a century ago. Despite this, several aspects of insulin engagement with its target and off-target receptors remain unknown, thus limiting the use of structure-guided design of novel analogs. A recent spurt in structural information for the insulin and insulin-like growth factor 1 receptors (IR and IGF-1R), were leveraged in this study to gain a deeper, molecular-level understanding of ligand recognition at these targets. Molecular dynamics (MD) and free energy perturbation (FEP) were utilized to map the drivers of potency and specificity of several insulin variants including disease-linked mutations. The remarkable accuracy of MD-FEP in capturing functional trends (>80% of cases) across various insulin analogs underscored the method’s potential. The ability to deconvolute observations into receptor contributions, conformational perturbations and (or) solvent-network changes lays the foundations for its use in predictive design of future insulins and other therapeutic peptides.

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Section: Discussionmentioning

confidence: 95%

Mapping Structural Drivers of Insulin Analogs Using Molecular Dynamics and Free Energy Calculations at Insulin Receptor

Sena

Gromiha

Chatterji

et al. 2022

Preprint

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“…2,63,64 For example, mutation of 704Arg residue of the IGF-1R receptor with Ala leads to decrease of IGF-1 binding by four times compared to wild-type receptor. 65 The equivalent residue in insulin is 19Tyr of A-chain which also involved in similar interactions with the non-cognate receptor. 63,66 Overall these simulations provided us with key interactions involved in the cognate/non-cognate complexes and could provide us with a framework to better understand the distinct engagement pattern of insulin and IGF-1 at the IGF-1R.…”

Section: Discussionmentioning

confidence: 99%

Mapping Structural Drivers of Insulin and its Analogs at the IGF-1 Receptor Using Molecular Dynamics and Free Energy Calculations

Sena,

Gromiha

et al. 2023

Preprint

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Insulin and insulin-like growth factor-1 receptors (IR, IGF-1R) belong to the family of receptor tyrosine kinases (RTKs), and share close structural resemblance. However, these receptors exhibit distinct activity profiles and functions in vivo. Binding of insulin to IGF-1R results in additional growth-factor-like behavior and cell proliferation, but its ∼100-fold reduced affinity to IGF-1R limits off-target activity. However, insulin analogs with increased potency at IGF-1R have oncogenicity as a key safety concern. Hence, the ability to accurately predict potency of novel analogs at IGF-1R could represent a key breakthrough towards rational insulin design. To date, a comprehensive molecular level understanding of insulin interactions at IGF-1R has remained elusive. This study capitalized on recent advancements in structural biology that provided high resolution structures of IGF-1R bound to IGF-1 and insulin. Initially, molecular dynamics (MD) simulations were employed to unravel the intricate interactions that characterize the receptor-ligand pairs. Next, free energy perturbation (FEP) calculations were performed to understand the increased affinity observed in insulin analogs, X10 and glargine. Subsequently, multiple mutations at the B10 position of insulin spanning different activities at IGF-1R and different metabolites of insulin glargine, encompassing various mitogenic potencies were studied using FEP. The calculations successfully captured directional shifts in potency for all studied mutants, with approximately 50% of the predicted values falling within 1 kcal/mol of experiment. Beyond its impressive accuracy, FEP’s ability to provide a detailed understanding of protein- and solvent-mediated contributions to the observed functional profiles underscores its utility in designing safe IGF-1R selective novel insulin analogs.

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“…Binding affinities of compounds for IRÀ A were determined by the competition with 125 I-TyrA14 human insulin for IRÀ A in human IM-9 lymphocytes (ATCC) as described previously. [38] Radiolabeled 125 I-TyrA14 human insulin was prepared according to a procedure described in detail by Asai et al [39] Binding affinities for IGF-1R were determined by the competition with human 125 I-IGF-1 for IGF-1R in mouse fibroblasts transfected with human IGF-1R and with deleted mouse IGF-1R according to Hexnerová et al [40] Radiolabeled 125 I-IGF-1 was prepared as described in Kertisova et al [41] All compounds were tested at 0.1 mM concentration for both receptors in duplicate points and if some binding was detected, the binding curve of the compound was determined, and dissociation constant (K d ) was calculated or estimated.…”

Section: Hand Sorting Of Fluorescent Beadsmentioning

confidence: 99%

Combinatorial Libraries of Bipodal Binders of the Insulin Receptor

Selicharová,

Fabre,

Soledad Garre Hernández

et al. 2024

ChemMedChem

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The binding process of insulin to its transmembrane receptor entails a sophisticated interplay between two proteins, each possessing two binding sites. Given the difficulties associated with the use of insulin in the treatment of diabetes, despite its remarkable efficacy, there is interest in smaller and more stable compounds than the native hormone that would effectively activate the receptor. Our study adopts a strategy focused on synthesizing extensive combinatorial libraries of bipodal compounds consisting of two distinct peptides linked to a molecular scaffold. These constructs, evaluated in a resin bead‐bound format, were designed to assess their binding to the insulin receptor. Despite notable nonspecific binding, our approach successfully generated and tested millions of compounds. Rigorous evaluations via flow cytometry and specific antibodies revealed peptide sequences with specific interactions at either receptor binding Site 1 or 2. Notably, these sequences bear similarity to peptides discovered through phage display by other researchers. This convergence of chemical and biological methods underscores nature's beauty, revealing general principles in peptide binding to the insulin receptor. Overall, our study deepens the understanding of molecular interactions in ligand binding to the insulin receptor, highlighting the challenges of targeting large proteins with small synthetic peptides.

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Insulin receptor Arg717 and IGF-1 receptor Arg704 play a key role in ligand binding and in receptor activation

Cited by 7 publications

References 50 publications

Mapping Structural Drivers of Insulin Analogs Using Molecular Dynamics and Free Energy Calculations at Insulin Receptor

Mapping Structural Drivers of Insulin Analogs Using Molecular Dynamics and Free Energy Calculations at Insulin Receptor

Mapping Structural Drivers of Insulin and its Analogs at the IGF-1 Receptor Using Molecular Dynamics and Free Energy Calculations

Combinatorial Libraries of Bipodal Binders of the Insulin Receptor

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