A sedimentation equilibrium study of platypus insulin: the HB10D mutant does not associate beyond dimer

Nourse, Amanda; Jeffrey, Peter D.

doi:10.1016/s0301-4622(97)00131-2

Cited by 5 publications

(4 citation statements)

References 36 publications

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“…Sequence variation from insulin, particularly at residues B10, 28, and 29, collectively reduces selfassociation and serves to maintain IGF-1 in a monomeric state. 20,22 The mutations within the midregion of the insulin B-chain of Tyr-Leu to Gln-Phe in IGF-1 effectively diminish activity at the insulin receptor, and its reversal provides high potency analogs. 23,24 Figure 2A shows the primary sequences of all insulin analogs analyzed in this study.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…It contains notable changes in the A-chain, which increase its relative hydrophilicity and solubility in physiological buffers. Sequence variation from insulin, particularly at residues B10, 28, and 29, collectively reduces self-association and serves to maintain IGF-1 in a monomeric state. , The mutations within the midregion of the insulin B-chain of Tyr-Leu to Gln-Phe in IGF-1 effectively diminish activity at the insulin receptor, and its reversal provides high potency analogs. , …”

Section: Results and Discussionmentioning

confidence: 99%

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Discovery of High Potency, Single-Chain Insulin Analogs with a Shortened B-Chain and Nonpeptide Linker

et al. 2013

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A series of novel, single chain insulin analogs containing polyethylene glycol based connecting segments were synthesized by native chemical ligation and tested for biological activity. While the full length single chain insulin analogs exhibited low potency, deletion of amino acids B26-B30 unexpectedly generated markedly higher activity. This observation is unprecedented in all previous studies of single chain insulin analogs and is consistent with the presumption that in the native hormone this sequence must translocate to achieve high potency insulin receptor interaction. Optimization of the sequence yielded an insulin analog with potency and selectivity comparable to that of native insulin. These results establish a basis for discovery of novel higher potency, single chain insulin analogs of shortened length.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Results and Discussionmentioning

confidence: 99%

Discovery of High Potency, Single-Chain Insulin Analogs with a Shortened B-Chain and Nonpeptide Linker

et al. 2013

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“…The values for the association constants to be gathered from the literature are scattered over a wide range that extends from to for and from 220 1/mol to for Pocker and Biswas, 1981;Mark et al, 1987;Nourse and Jeffrey, 1998;. As it is not intended here to fit measured data, and were used as representative values for demonstrating the scheme.…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, it seems that in the absence of electrostatic repulsion the scheme in Figure 1 basically applies. The two-contact concept has been followed up and applied successfully by Jeffrey and coworkers, though without emphasis on the keystone effect (Mark et al, 1987;Nourse and Jeffrey, 1998). However, a question is left open that has intrigued us all the time: as any association beyond the classical dimer depends on the weak contact, how can tetramers form, whereas alternative dimers D' have never really been shown to exist?…”

Section: Introductionmentioning

confidence: 99%

Insulin & Related Proteins - Structure to Function and Pharmacology

Dieken¹,

Federwisch²,

Meyts³

2002

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Arginine dipeptides affect insulin aggregation in a pH‐ and ionic strength‐dependent manner

Nuhu

Curtis

2015

Biotechnology Journal

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Solutions containing arginine or mixtures of arginine and other amino acids are commonly used for protein liquid formulations to overcome problems such as high viscosities, aggregation, and phase separation. The aim of this work is to examine whether the stabilizing properties of arginine can be improved by incorporating the amino acid into a dipeptide. A series of arginine-containing dipeptides have been tested for their ability to suppress insulin aggregation over a range of pH and ionic strength. The aggregation is monitored at room temperature using a combination of turbidimetry and light scattering for solutions at pH 5.5 or 3.7, whereas thermal-induced aggregation is measured at pH 7.5. In addition, intrinsic fluorescence has been used to quantify additive binding to insulin. The dipeptide diArg is the most effective additive in solutions at pH 5.5 and 3.7, whereas the dipeptide Arg-Phe almost completely eliminates thermally-induced aggregation of insulin at pH 7.5 up to temperature of 90°C. Insulin has been chosen as a model system because the molecular forces controlling its aggregation are well known. From this understanding, we are able to provide a molecular basis for how the various dipeptides affect insulin aggregation.

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A sedimentation equilibrium study of platypus insulin: the HB10D mutant does not associate beyond dimer

Cited by 5 publications

References 36 publications

Discovery of High Potency, Single-Chain Insulin Analogs with a Shortened B-Chain and Nonpeptide Linker

Discovery of High Potency, Single-Chain Insulin Analogs with a Shortened B-Chain and Nonpeptide Linker

Insulin & Related Proteins - Structure to Function and Pharmacology

Arginine dipeptides affect insulin aggregation in a pH‐ and ionic strength‐dependent manner

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