Crystal structure of destripeptide (B28–B30) insulin: implications for insulin dissociation

Ye, Jun; Chang, Wenrui; Liang, Dongcai

doi:10.1016/s0167-4838(01)00160-1

Cited by 5 publications

(2 citation statements)

References 21 publications

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“…The first and foremost conclusion of structural studies of insulin is that the protein is extremely flexible and adaptable. Numerous crystal forms depending on their specific T and R conformations are known (Chothia et al 1983;Hua et al 1991;Hawkins et al 1994Hawkins et al , 1995Ye et al 1996Ye et al , 2001Bao et al 1997;Whittingham et al 1997;Schlein et al 2000;Dupradeau et al 2002). The flexibility is especially marked in the B chain: The conformation of the N terminus gives rise to the T and R naming system, and the flexibility of the C terminus is thought to be very important in a conformational change necessary for receptor binding.…”

Section: Insulinmentioning

confidence: 99%

Normal modes for predicting protein motions: A comprehensive database assessment and associated Web tool

2005

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We carry out an extensive statistical study of the applicability of normal modes to the prediction of mobile regions in proteins. In particular, we assess the degree to which the observed motions found in a comprehensive data set of 377 nonredundant motions can be modeled by a single normal-mode vibration. We describe each motion in our data set by vectors connecting corresponding atoms in two crystallographically known conformations. We then measure the geometric overlap of these motion vectors with the displacement vectors of the lowest-frequency mode, for one of the conformations. Our study suggests that the lowest mode contains useful information about the parts of a protein that move most (i.e., have the largest amplitudes) and about the direction of this movement. Based on our findings, we developed a Web tool for motion prediction (available from http://molmovdb.org/nma) and apply it here to four representative motions-from bacteriorhodopsin, calmodulin, insulin, and T7 RNA polymerase.In the analysis of protein dynamics, an important goal is the description of slow large-amplitude motions. These motions, while strongly damped, typically describe conformational changes which are essential for the functioning of proteins. Only global collective motions can significantly change the exposed surface of the protein and hence influence interactions with its environment. Such structural rearrangements in the protein can occur on a local level within a single domain or can involve large movements of protein domains in a multidomain protein. Protein dynamics thus cover a broad timescale: 10 −14 -10 sec (Wilcox et al. 1988). However, many large-amplitude conformational changes are not on a timescale accessible by most timedependent theoretical methods, such as phase space sampling techniques (e.g., molecular dynamics). Therefore, in order to gain insight into the mechanism of slow, largeamplitude motions, one must resort to the use of a timeindependent approach, such as normal mode analysis (Levitt et al. 1985).Normal mode analysis (NMA) is a fast and simple method to calculate vibrational modes and protein flexibility. In NMA, sometimes restrained to C␣ atoms only, the atoms are modeled as point masses connected by springs, which represent the interatomic force fields. One particular type of NMA is the elastic network model. In this model, the springs connecting each node to all other neighboring nodes are of equal strength, and only the atom pairs within a cutoff distance are considered.All existing NMA techniques have important common limitations resulting from the use of the harmonic approximation, the neglect of solvent damping, and the absence of information about energy barriers and multiple minima on the potential energy surface (Elber and Karplus 1987;Frauenfelder et al. 1988;Hong et al. 1990). In fact, the most interesting biologically significant low-frequency motions in a realistic environment are overdamped and hence not vibrational at all, rendering the corresponding normal mode frequencies of ...

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Section: Insulinmentioning

confidence: 99%

Normal modes for predicting protein motions: A comprehensive database assessment and associated Web tool

2005

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“…The SA of Phe B24 and Tyr B26 in such hexamers is negligible. Also, on hexamer assembly, Pro B28 (which stabilizes the dimer interfaces within the HI hexamer via hydrophobic interactions with Gly B20 , Glu B21 and Gly B23 (24,25)) exhibited a decrease in oxidation rate of 2.4-and 2.0-fold for HI and HPI hexamers, respectively. An intriguing discrepancy was inferred at position B28 as its SA, calculated from our HPI models, exhibited a less marked decrease in the HPI hexamer relative to that predicted by the HI T 6 crystal structure.…”

Section: Resultsmentioning

confidence: 99%

Structural Analysis of Proinsulin Hexamer Assembly by Hydroxyl Radical Footprinting and Computational Modeling

Kiselar

Datt

Chance

et al. 2011

Journal of Biological Chemistry

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Background: Proinsulin, an intermediate in insulin biosynthesis, is refractory to crystallization. Results: Synchrotron-based hydroxyl radical footprints of proinsulin were obtained in relation to classical structures of insulin. Conclusion: Molecular models based on footprinting provide evidence for native self-assembly and an ensemble of C-domain orientations. Significance: Footprinting promises to enable analysis of toxic aggregation of clinical proinsulin variants in neonatal diabetes mellitus.

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Insulin

Smith

2004

Handbook of Metalloproteins

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The protein hormone insulin, produced in the pancreas and stored in granules, interacts, after secretion into the blood stream, with the extracellular domain of the insulin receptor. This interaction initializes a signal transduction cascade that ultimately results in glucose absorption and metabolism. In the presence of zinc ion, insulin crystallizes as a threefold symmetric T 6 hexamer complexed to two zinc ions. When phenol, m ‐cresol, or resorcinol is present in the crystallizing media, the first eight residues of all B‐chains undergo a conformational change from extended to α‐helical producing an R 6 hexamer. In the presence of thiocyanate or chloride ion, only residues 4 through 8 in the B‐chains of one trimer undergo the conformational change to produce a T 3 R 3 f hexamer. This allosteric behavior of the insulin hexamer has been observed in the solid state as well as in solution. Like the T 6 hexamer, each zinc ion that lies on the crystallographic threefold axis is octahedrally coordinated by NE2s of three symmetry related HisB10 residues and three water molecules. Because of the conformational transition from T to either R or R f , there is not sufficient space in an R‐ or R f ‐state trimer to accommodate octahedral coordination, and, therefore, zinc adopts tetrahedral coordination through bonds to the three symmetry related HisB10 NE2 atoms and either to a water molecule or to a chloride ion. In the case of T 3 R 3 f hexamers, three additional zinc binding sites exist between symmetry related R f ‐state monomers in which each zinc ion is coordinated by NE2 of a second orientation of the side chain of HisB10, NE2 of HisB5 of an adjacent monomer, and two chloride ions. From a total of 34 crystal structures of hexameric insulin, mean ZnNE2 bond distances of 2.00 or 2.10 Å are observed in tetrahedral or octahedral geometry, respectively.

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Crystal structure of destripeptide (B28–B30) insulin: implications for insulin dissociation

Cited by 5 publications

References 21 publications

Normal modes for predicting protein motions: A comprehensive database assessment and associated Web tool

Normal modes for predicting protein motions: A comprehensive database assessment and associated Web tool

Structural Analysis of Proinsulin Hexamer Assembly by Hydroxyl Radical Footprinting and Computational Modeling

Insulin

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