Landmarks in Insulin Research

Ward, Colin W.; Lawrence, Michael C.

doi:10.3389/fendo.2011.00076

Cited by 41 publications

(32 citation statements)

References 101 publications

(122 reference statements)

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“…Each monomer in the receptor homo‐dimer is comprised of two leucine‐rich domains (L1 and L2) separated by a cysteine‐rich (CR) domain and followed by three fibronectin type‐III repeats, F1, F2, and F3, which is connected via a single transmembrane helix to the intracellular kinase domain 6. Although the molecular details of insulin binding and receptor activation remain elusive, partly due to the lack of structure of the hormone‐bound receptor, the crystal structure of apo‐IR (IR $\Delta \beta$ 7; PDB code 2DTG) has provided structural bases for domain organization in the IR homodimer,8–13 where subunits are arranged in a “folded‐over inverted V” conformation with each of the two insulin‐binding pockets formed by the (L1–CR–L2) motif of one subunit and the (F1–F2–F3) motif of the other subunit. A homology model of the IGF1R ectodomain validated by small‐angle X‐ray scattering (SAXS) data displays similar overall architecture 14…”

Section: Introductionmentioning

confidence: 99%

All‐atom structural models of insulin binding to the insulin receptor in the presence of a tandem hormone‐binding element

Vashisth

Abrams

2013

Proteins

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Insulin regulates blood glucose levels in higher organisms by binding to and activating insulin receptor (IR), a constitutively homodimeric glycoprotein of the receptor tyrosine kinase (RTK) superfamily. Therapeutic efforts in treating diabetes have been significantly impeded by the absence of structural information on the activated form of the insulin/IR complex. Mutagenesis and photo-crosslinking experiments and structural information on insulin and apo-IR strongly suggest that the dual-chain insulin molecule, unlike the related single-chain insulin-like growth factors, binds to IR in a very different conformation than what is displayed in storage forms of the hormone. In particular, hydrophobic residues buried in the core of the folded insulin molecule engage the receptor. There is also the possibility of plasticity in the receptor structure based on these data, which may in part be due to rearrangement of the so-called CT-peptide, a tandem hormone-binding element of IR. These possibilities provide opportunity for large-scale molecular modeling to contribute to our understanding of this system. Using various atomistic simulation approaches, we have constructed all-atom structural models of hormone/receptor complexes in the presence of CT in its crystallographic position and a thermodynamically favorable displaced position. In the "displaced-CT" complex, many more insulin-receptor contacts suggested by experiments are satisfied, and our simulations also suggest that R-insulin potentially represents the receptor-bound form of hormone. The results presented in this work have further implications for the design of receptor-specific agonists/antagonists.

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Section: Introductionmentioning

confidence: 99%

All‐atom structural models of insulin binding to the insulin receptor in the presence of a tandem hormone‐binding element

Vashisth

Abrams

2013

Proteins

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“…The importance of the 3 insulin disulfides and the aromatic amino acids (B24, B25, and A19) in insulin function are well-established (Murray-Rust et al, 1992). Mutagenesis data indicated that a second receptor-binding surface is present on insulin that involves residues A12 (S), A13 (L), A17 (E), B10 (H), B13 (D), and B17 (L) (Ward and Lawrence, 2011). Multiple alignment analyses showed that the amino acid sequence of the B-chain of Alligator sinensis and birds differed at some sites, such as B13, B21, and B30.…”

Section: Discussionmentioning

confidence: 99%

Full-length cDNA cloning and structural characterization of preproinsulin in Alligator sinensis

Zhang

et al. 2014

Genet. Mol. Res.

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ABSTRACT.Insulin is an important endocrine hormone that plays a critical physiological role in regulating metabolism and glucostasis in vertebrates. In this study, the complete cDNA of Alligator sinensis preproinsulin gene was cloned for the first time by reverse transcriptionpolymerase chain reaction and rapid amplification of cDNA ends methods; the amino acid sequence encoded and protein structure were analyzed. The full-length of preproinsulin cDNA sequence consists of 528 base pairs (bp), comprising a 34-bp 5'-untranslated region, a 170-bp 3'-untranslated region and an open reading frame that is 324 bp in length. The open reading frame encodes a 107-amino acid preproinsulin with a molecular weight of approximately 12,153.8 Da, theoretical isoelectric point of 5.68, aliphatic index of 92.06, and grand average of hydropathicity of -0.157, from which a signal peptide, a B-chain, a C-peptide, and an A-chain are derived. Online analysis suggested that the deduced preproinsulin amino acid sequence contains a transmembrane region, and that it has a signal peptide whose cleavage site occurs between alanine 24 and alanine 25. Comparative analysis of preproinsulin amino acid sequences indicated that the A-chain and B-chain sequences of preproinsulins are highly conserved between reptiles and birds, and that the preproinsulin amino acid sequence of Alligator sinensis shares 89% similarity to that of Chelonia mydas, but low similarity of 48-63% to those of mammals and fishes. The phylogenetic tree constructed using the neighbor-joining method revealed that preproinsulin of Alligator sinensis had high homology with reptiles and birds, such as Chelonia mydas, Gallus gallus, and Columba livia.

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“…показали, что ИР представляет собой тетрамер, образованный двумя α-и двумя β-субъединицами, соединенными ди-сульфидными мостиками (см. рисунок) [13]. ИР от-носится к трансмембранным гликопротеинам, α-субъ-еди ницы которого находятся во внеклеточной обла-сти и отвечают за связывание инсулина, а β-субъ-единицы образуют внутриклеточный домен, цито-плазматическая область которого содержит тиро-зинкиназный домен, с помощью которого фосфо-рилируются внутриклеточные белки-субстраты ин-сулинового сигнального пути по специфическим аминокислотным остаткам тирозина [14].…”

Section: строение инсулинового рецептораunclassified

Promising pharmacological targets for the treatment of the diseases associated with the impaired insulin receptor signaling pathway

Gorbunov

Brigadirova

Качаева

et al. 2015

Probl Endokrinol (Mosk)

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ОБЗОРЫСахарный диабет (СД) занимает одно из первых мест в мире среди наиболее распространенных хро-нических заболеваний. В ряд социально значимых заболеваний СД ставят такие его особенности, как большая частота встречаемости, высокий риск ин-валидизации и смертности больных. В 2013 г., по данным Международной диабетической федерации, численность больных СД в мире составила 386 млн человек. Учитывая темпы распространения заболе-вания, согласно прогнозам экспертов ВОЗ, число пациентов с диагнозом СД достигнет к 2035 г. 592 млн человек в основном за счет больных СД 2-го типа (СД2) [1]. По данным Минздрава России, уро-вень инвалидизации по причине СД составляет 2,1 случая на 100 тыс. населения [2].СД представляет собой гетерогенную группу ме-таболических расстройств, которые характеризуют-ся общим симптомом -хронической гиперглике-мией, а также абсолютным или относительным де-фицитом продукции инсулина, либо его действия [3]. СД 1-го типа возникает из-за недостаточной продукции инсулина вследствие потери функцио- Diabetes mellitus (DM) is one of the most widespread chronic diseases in the world. In DM type 2, peripheral tissues demonstrate strong resistance to endogenous insulin (insulin resistance) which is caused by impaired ability of the hormone to stimulate glucose uptake in target cells (muscle, adipose or brain tissue, liver, etc.) and to reduce blood glucose level. Research data suggest that all mentioned reasons are most likely to be based on a disruption of signal transduction from insulin receptor (IR) into insulin-dependent intracellular signaling cascades. Contemporary DM treatment strategy is aimed at the maintenance of optimal blood glucose level by improving insulin production and increasing insulin sensitivity of tissue as well as prevention of macro-and microvascular complications and decrease of their intensity. At the same time, the search for new targets for creation of innovative anti-diabetic compounds can be considered a promising task due to the optimization of existing approaches and development of the novel ones taking into account results of the latest research into DM etiology and pathogenesis. A special position among possible targets is occupied by insulin receptor (IR) and IR-associated signaling pathways. Belonging to tyrosine kinase receptor family, IR has been actively studied during the last decades. This review considers in particular the IR structure and functioning of receptor-associated signaling pathways. The paper contains data on novel ligand-mimetics and IR sensitizers as well as other molecules, which affect different components of IR-associated signaling pathways, thus exerting significant antidiabetic effect. Action of these compounds is aimed at improvement of basic metabolic disorders resulting in hyperglycemia and is mainly carried out due to the following effects: activation and potentiation of insulin signaling, increase of insulin sensitivity of peripheral tissues; recovery of insulin secretion physiological mechanisms; reduction of glucose production in liver.

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Landmarks in Insulin Research

Cited by 41 publications

References 101 publications

All‐atom structural models of insulin binding to the insulin receptor in the presence of a tandem hormone‐binding element

All‐atom structural models of insulin binding to the insulin receptor in the presence of a tandem hormone‐binding element

Full-length cDNA cloning and structural characterization of preproinsulin in Alligator sinensis

Promising pharmacological targets for the treatment of the diseases associated with the impaired insulin receptor signaling pathway

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