Jerez A Te

Mayo Clinic - Scottsdale, Scottsdale, Arizona, United States

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Publications (8)22.9 Total impact

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    ABSTRACT: Proteomics techniques have revealed that lysine acetylation is abundant in mitochondrial proteins. This study was undertaken 1) to determine the relationship between mitochondrial protein acetylation and insulin sensitivity in human skeletal muscle, identifying key acetylated proteins, and 2) to use molecular modeling techniques to understand the functional consequences of acetylation of adenine nucleotide translocase 1 (ANT1), which we found to be abundantly acetylated. Eight each lean and obese nondiabetic subjects had euglycemic clamps and muscle biopsies for isolation of mitochondrial proteins and proteomics analysis. A number of acetylated mitochondrial proteins were identified in muscle biopsies. Overall, acetylation of mitochondrial proteins was correlated with insulin action (r = 0.60, P < 0.05). Of the acetylated proteins, ANT1, which catalyzes ADP/ATP exchange across the inner mitochondrial membrane, was acetylated at lysines 10, 23, and 92. Acetylation of lysine 23 decreased following exercise, depending on insulin sensitivity. Molecular dynamics modeling and ensemble docking simulations predicted the ADP binding site of ANT1 to be a pocket of positively charged residues, including lysine 23. Calculated ADP/ANT1 binding affinities were physiologically relevant and predicted substantial reductions in affinity upon lysine 23 acetylation. Insertion of these derived binding affinities as parameters into a complete mathematical description of ANT1 kinetics predicted marked reductions in adenine nucleotide flux resulting from lysine 23 acetylation. Therefore, acetylation of ANT1 could have dramatic physiological effects on ADP/ATP exchange. Dysregulation of acetylation of mitochondrial proteins such as ANT1 therefore could be related to changes in mitochondrial function that are associated with insulin resistance.
    Biochemistry 06/2014; · 3.38 Impact Factor
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    ABSTRACT: Computational prediction of the effects of residue changes on peptide-protein binding affinities, followed by experimental testing of the top predicted binders, is an efficient strategy for the rational structure-based design of peptide inhibitors. In this study we apply this approach to the discovery of competitive antagonists for the secretin receptor, the prototypical member of class B G protein-coupled receptors (GPCRs). Proteins in this family are involved in peptide hormone-stimulated signaling and are implicated in several human diseases, making them potential therapeutic targets. We first validated our computational method by predicting changes in the binding affinities of several peptides to their cognate class B GPCRs due to alanine replacement and compared the results with previously published experimental values. Overall, the results showed a significant correlation between the predicted and experimental ΔΔG values. Next, we identified candidate inhibitors by applying this method to a homology model of the secretin receptor bound to an N-terminal truncated secretin peptide. Predictions were made for single residue replacements to each of the other nineteen naturally occurring amino acids at peptide residues within the segment binding the receptor N-terminal domain. Amino acid replacements predicted to most enhance receptor binding were then experimentally tested by competition-binding assays. We found two residue changes that improved binding affinities by almost one log unit. Furthermore, a peptide combining both of these favorable modifications resulted in an almost two log unit improvement in binding affinity, demonstrating the approximately additive effect of these changes on binding. In order to further investigate possible physical effects of these residue changes on receptor binding affinity, molecular dynamics simulations were performed on representatives of the successful peptide analogues (namely A17I, G25R, and A17I/G25R) in bound and unbound forms. These simulations suggested that a combination of the α-helical propensity of the unbound peptide and specific interactions between the peptide and the receptor extracellular domain contribute to their higher binding affinities.
    Journal of Computer-Aided Molecular Design 05/2012; 26(7):835-45. · 3.17 Impact Factor
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    ABSTRACT: The natural ligands for family B G protein-coupled receptors are moderate-length linear peptides having diffuse pharmacophores. The amino-terminal regions of these ligands are critical for biological activity, with their amino-terminal truncation leading to production of orthosteric antagonists. The carboxyl-terminal regions of these peptides are thought to occupy a ligand-binding cleft within the disulfide-bonded amino-terminal domains of these receptors, with the peptides in amphipathic helical conformations. In this work, we have characterized the binding and activity of a series of 11 truncated and lactam-constrained secretin(5-27) analogues at the prototypic member of this family, the secretin receptor. One peptide in this series with lactam connecting residues 16 and 20 [c[E(16),K(20)][Y(10)]sec(5-27)] improved the binding affinity of its unconstrained parental peptide 22-fold while retaining the absence of endogenous biological activity and competitive antagonist characteristics. Homology modeling with molecular mechanics and molecular dynamics simulations established that this constrained peptide occupies the ligand-binding cleft in an orientation similar to that of natural full-length secretin and provided insights into why this peptide was more effective than other truncated conformationally constrained peptides in the series. This lactam bridge is believed to stabilize an extended α-helical conformation of this peptide while in solution and not to interfere with critical residue-residue approximations while docked to the receptor.
    Biochemistry 08/2011; 50(38):8181-92. · 3.38 Impact Factor
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    ABSTRACT: Secretin is a linear 27-residue peptide hormone that stimulates pancreatic and biliary ductular bicarbonate and water secretion by acting at its family B G protein-coupled receptor. While, like other family members, the carboxyl-terminal region of secretin is most important for high affinity binding and its amino-terminal region is most important for receptor selectivity and receptor activation, determinants for these activities are distributed throughout the entire length of this peptide. In this work, we have systematically investigated changing each residue within secretin to alanine and evaluating the impact on receptor binding and biological activity. The residues most critical for receptor binding were His1, Asp3, Gly4, Phe6, Thr7, Ser8, Leu10, Asp15, Leu19, and Leu23. The residues most critical for biological activity included His1, Gly4, Thr7, Ser8, Glu9, Leu10, Leu19, Leu22, and Leu23, with Asp3, Phe6, Ser11, Leu13, Asp15, Leu26, and Val27 also contributing. While the importance of residues in positions analogous to His1, Asp3, Phe6, Thr7, and Leu23 is conserved for several closely related members of this family, Leu19 is uniquely important for secretin. We, therefore, have further studied this residue by molecular modeling and molecular dynamics simulations. Indeed, the molecular dynamics simulations showed that mutation of Leu19 to alanine was destabilizing, with this effect greater than that observed for the analogous position in the other close family members. This could reflect reduced contact with the receptor or an increase in the solvent-accessible surface area of the hydrophobic residues in the carboxyl terminus of secretin as bound to its receptor.
    Biochemistry 03/2011; 50(14):2983-93. · 3.38 Impact Factor
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    Jerez A Te, Toshiko Ichiye
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    ABSTRACT: The effects of water multipole moments on the aqueous solvation of ions were determined in Monte Carlo simulations using soft-sticky dipole-quadrupole-octupole (SSDQO) water. Water molecules formed linear hydrogen bonds to Cl(-) using the new SSDQO1 parameters, similar to multi-site models. However, the dipole vector was tilted rather than parallel to the oxygen-Na(+) internuclear vector as in most multi-site model, while experiment and ab initio molecular dynamics simulations generally indicate a range of values between tilted and parallel. By varying the multipoles in SSDQO, the octupole was found to determine the orientation around Na(+). Moreover, analysis of the multipoles of more conventional models is predictive of their performance as solvents.
    Chemical Physics Letters 10/2010; 499(4-6):219-225. · 2.15 Impact Factor
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    ABSTRACT: Water structure around sugars modeled by partial charges is compared for soft-sticky dipole-quadrupole-octupole (SSDQO), a fast single-site multipole model, and commonly used multi-site models in Monte Carlo simulations. Radial distribution functions and coordination numbers of all the models indicate similar hydration by hydrogen-bond donor and acceptor waters. However, the new optimized SSDQO1 parameters as well as TIP4P-Ew and TIP5P predict a "lone-pair" orientation for the water accepting the sugar hydroxyl hydrogen bond that is more consistent with the limited experimental data than the "dipole" orientation in SPC/E, which has important implications for studies of the cryoprotectant properties of sugars.
    Chemical Physics Letters 05/2010; 491(4-6):218-223. · 2.15 Impact Factor
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    Jerez A Te, Toshiko Ichiye
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    ABSTRACT: The soft-sticky dipole-quadrupole-octupole (SSDQO) potential energy function for a coarse-grained single-site water model has Lennard-Jones interactions and an approximate multipole expansion for the electrostatics. Here, the Lennard-Jones parameters and multipole moments of SSDQO were optimized so that the structural, thermodynamic, dynamic, and dielectric properties agreed with experimental values of liquid water at ambient conditions. Using these parameters, the temperature and pressure dependence of various properties were shown to be in good agreement with experiment, including a temperature of maximum density at approximately 260 K. This new parametrization, referred to as SSDQO1, is both computationally faster and generally more accurate over a wide range of conditions than traditional three-site water models, which demonstrates that a model with a single dipole, quadrupole, and octupole on each water molecule can reproduce the tetrahedral hydrogen bonded network of water.
    The Journal of Chemical Physics 03/2010; 132(11):114511. · 3.16 Impact Factor
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    ABSTRACT: The soft sticky dipole-quadrupole-octupole (SSDQO) potential energy function represents a water molecule by a single site with a van der Waals sphere and point multipoles. Previously, SSDQO was shown to give good properties for liquid water and solvation of simple ions and is faster than three point models. Here, SSDQO is assessed for solvating biologically relevant molecules having a multi-site, partial charge description. Monte Carlo simulations of ethanol, benzene, and N-methylacetamide in SSDQO with SPC/E moments showed the water structure was as good as in SPC/E. Thus, SSDQO is potentially useful for simulations of biological macromolecules in aqueous solution.
    Chemical Physics Letters 02/2010; 486(1-3):70-73. · 2.15 Impact Factor