Mapping the Functional Surface of Insulin by Design: Structure and Function of a Novel A-Chain Analogue

Hua, Qing; Frank, Bruce H.; Jia, Wenhua; Chen, Ying; Wang, Shu Hua; Burke, G. Thompson; Katsoyannis, Panayotis G.; Weiss, Michael A.

doi:10.1006/jmbi.1996.0648

Cited by 115 publications

(212 citation statements)

References 62 publications

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“…The NMR structures of the monomeric form of insulin, facilitated by mutations (12)(13)(14) or truncations of the B-chain (15,16), have confirmed both the conformations known from the inactive forms of the hormone and the intrinsic mobility of the N and C termini of the B-chain. Systematic photo-cross-linking mapping of the photo-activated surface of insulins in complexes with the IR have provided further insight into the role of the individual hormone side chains for stability of the insulin-IR interface (17,18).…”

mentioning

confidence: 71%

Structural Integrity of the B24 Site in Human Insulin Is Important for Hormone Functionality

Žáková

Kletvíková

Veverka

et al. 2013

Journal of Biological Chemistry

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Background:The structure of the C-terminal B21-B30 chain of insulin bound to the insulin receptor remains undetermined. Results: The structures of B24-modified insulins were determined. Conclusion: The structural integrity of Phe B24 but flexibility of B25-B30 insulin residues are important for receptor binding. Significance: The knowledge of the receptor-bound structure of insulin is important for the design of new insulin receptor agonists.

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confidence: 71%

Structural Integrity of the B24 Site in Human Insulin Is Important for Hormone Functionality

Žáková

Kletvíková

Veverka

et al. 2013

Journal of Biological Chemistry

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“…Spectra were obtained at 600 MHz at 25°C (pH 3.7 and 7.3) as described in Hua et al (1996); the protein concentration was 1.5 mM. Resonance assignment was based on 2D NOESY (mixing times 100 and 200 msec), TOCSY, and DQF-COSY spectra.…”

Section: Nmr Spectroscopymentioning

confidence: 99%

A divergent INS protein inCaenorhabditis elegansstructurally resembles human insulin and activates the human insulin receptor

et al. 2003

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Caenorhabditis elegans contains a family of putative insulin-like genes proposed to regulate dauer arrest and senescence. These sequences often lack characteristic sequence features of human insulin essential for its folding, structure, and function. Here, we describe the structure and receptor-binding properties of INS-6, a singlechain polypeptide expressed in specific neurons. Despite multiple nonconservative changes in sequence, INS-6 recapitulates an insulin-like fold. Although lacking classical receptor-binding determinants, INS-6 binds to and activates the human insulin receptor. Its activity is greater than that of an analogous single-chain human insulin analog. Received November 12, 2002; revised version accepted January 24, 2003. Development of Caenorhabditis elegans can arrest to form a specialized third-stage larva. Such dauer ("enduring") larvae can survive up to eight times longer than the organism's normal 2-wk lifespan (Blaxter and Bird 1997). An adaption to limited food supply, increased population density, or elevated temperature (Riddle and Albert 1997), the dauer stage is triggered by chemosensory cues under the joint control of insulin-related and TGF-␤-related signaling pathways (Ren et al. 1996;Kimura et al. 1997). On sensing favorable conditions for growth and reproduction, the dauer resumes development into adulthood. Genetic screens for dauer arrest have led to identification of C. elegans orthologs of the insulin receptor (daf-2) and post-receptor signaling pathway, including the catalytic subunit of PI-3-kinase (age-1), serine-threonine kinases Akt/PKB (akt-1 and akt-2) and a forkhead transcription factor (daf-16; Guarente and Although genetic screens for diapause or long-lived phenotypes did not reveal DAF-2 ligands, search of the C. elegans genome by sequence-and structure-based algorithms has uncovered a family of 37 putative insulinrelated (ins) genes (Pierce et al. 2001). These sequences are classified into three classes, designated ␣, ␤, and ␥, based on pattern of cysteines (Pierce et al. 2001). ␣-Class proteins lack an A6-A11 disulfide bridge, an invariant feature of vertebrate insulins and insulin-like growth factors (Baker et al. 1988). ␤-Class proteins appear to retain insulin's three canonical disulfide bridges, plus a fourth, whose location is variable. ␥-Class proteins contain three canonical (or pseudo-canonical) disulfide bridges. Because these sequences diverge from mammalian insulins at conserved sites required for biological activity, their classification as insulin-like has been presumptive. Genetic evidence is provided elsewhere in this issue that an ins gene (daf-28) functions in the daf-2 pathway of dauer arrest (Li et al. 2003).We describe here the chemical synthesis and structure of a ␤-class INS protein. Because it lacks dibasic processing sites (as utilized in cleavage of proinsulin; Steiner 1998), the protein was prepared as a single chain. The polypeptide folds to form a well-defined structure with four disulfide bridges. Despite marked sequence divergen...

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“…In mature insulin the folded zinc-insulin hexamer can appear in two different states: the T-state wherein residues B9 -B19 are ␣-helical and residues B1-B8 adopt extended (B1-B6) and turn (B7-B10) conformations; and the R-state wherein the ␣-helix starts at or near the N terminus and continues to residue B19 (9,10). In the native T state, which is the dominant conformation of the insulin monomer in solution (9,11,12), the glycine at B8 participates in the B7-B10 ␤ turn (turn 1) and exhibits a positive dihedral angle as is typical of D-amino acids (7,8,13,14).…”

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confidence: 99%

Deciphering a Molecular Mechanism of Neonatal Diabetes Mellitus by the Chemical Synthesis of a Protein Diastereomer, [d-AlaB8]Human Proinsulin

Avital-Shmilovici

Whittaker²,

Weiss

et al. 2014

Journal of Biological Chemistry

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Mapping the Functional Surface of Insulin by Design: Structure and Function of a Novel A-Chain Analogue

Cited by 115 publications

References 62 publications

Structural Integrity of the B24 Site in Human Insulin Is Important for Hormone Functionality

Structural Integrity of the B24 Site in Human Insulin Is Important for Hormone Functionality

A divergent INS protein inCaenorhabditis elegansstructurally resembles human insulin and activates the human insulin receptor

Deciphering a Molecular Mechanism of Neonatal Diabetes Mellitus by the Chemical Synthesis of a Protein Diastereomer, [d-AlaB8]Human Proinsulin

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