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151.
Davide Comoletti Alexander Grishaev Andrew E. Whitten Palmer Taylor Jill Trewhella 《Chemico-biological interactions》2008,175(1-3):150
Neuroligins are post-synaptic cell adhesion molecules that promote synaptic maturation and stabilization upon binding with pre-synaptic partners, the α- and β-neurexins. Using a combination of analytical ultracentrifugation, small angle X-ray, and neutron scattering, we have characterized the low-resolution three-dimensional structure of the extracellular domain of the neuroligins, free in solution, and in complex with β-neurexin. The globular extracellular domain of the neuroligins forms stable homodimers through a four-helix bundle typical of the cholinesterases and other members of the α/β-hydrolase fold family. The presence of the stalk region adds to the extracellular domain of neuroligin-1 an elongated structure, suggesting a rod-like nature of the stalk domain. Sedimentation equilibrium coupled with solution scattering data of the β-neurexin/neuroligin-1 complex indicated a 2:2 stoichiometry where two β-neurexin molecules bind to a neuroligin-1 dimer. Deuteration of neurexin allowed us to collect neutron scattering data that, in combination with other biochemical techniques, provide a basis for optimizing the positioning of each component in a detailed computational model of the neuroligin/neurexin complex. As several mutations of both neurexin and neuroligin genes have been linked to autism spectrum disorders and mental retardation, these new structures provide an important framework for the study of altered structure and function of these synaptic proteins. 相似文献
152.
Comoletti D Grishaev A Whitten AE Taylor P Trewhella J 《Chemico-biological interactions》2008,175(1-3):150-155
Neuroligins are post-synaptic cell adhesion molecules that promote synaptic maturation and stabilization upon binding with pre-synaptic partners, the alpha- and beta-neurexins. Using a combination of analytical ultracentrifugation, small angle X-ray, and neutron scattering, we have characterized the low-resolution three-dimensional structure of the extracellular domain of the neuroligins, free in solution, and in complex with beta-neurexin. The globular extracellular domain of the neuroligins forms stable homodimers through a four-helix bundle typical of the cholinesterases and other members of the alpha/beta-hydrolase fold family. The presence of the stalk region adds to the extracellular domain of neuroligin-1 an elongated structure, suggesting a rod-like nature of the stalk domain. Sedimentation equilibrium coupled with solution scattering data of the beta-neurexin/neuroligin-1 complex indicated a 2:2 stoichiometry where two beta-neurexin molecules bind to a neuroligin-1 dimer. Deuteration of neurexin allowed us to collect neutron scattering data that, in combination with other biochemical techniques, provide a basis for optimizing the positioning of each component in a detailed computational model of the neuroligin/neurexin complex. As several mutations of both neurexin and neuroligin genes have been linked to autism spectrum disorders and mental retardation, these new structures provide an important framework for the study of altered structure and function of these synaptic proteins. 相似文献
153.
Whitten ST Yang HW Fox RO Hilser VJ 《Protein science : a publication of the Protein Society》2008,17(7):1200-1211
The left-handed polyproline II helical structure (P(II)) is observed to be a dominant conformation in the disordered states of protein and small polypeptide chains, even when no prolines are present in the sequence. Recently, in work by Ferreon and Hilser, the energetics associated with Ala and Gly substitutions at a surface exposed proline site were determined calorimetrically by measuring the binding energetics of Sos peptide variants to the C-terminal Src Homology 3 domain of SEM-5. The results were interpreted as a significant conformational bias toward the bound conformation (i.e., P(II)), even when the ligand is unbound. That study was not able to determine, however, whether the conformational bias of the peptides could be explained in terms other than that of a P(II) preference. Here, we test, using a computer algorithm based on the hard sphere collision (HSC) model, the notion of whether a bias in the unbound states of the peptide ligands is specific for the P(II) conformation, or if a bias to any other region of (phi, psi) space can also result in the same observed binding energetics. The results of these computer simulations indicate that, of the regions of (phi, psi) modeled for bias in the small peptides, only the bias to the P(II) conformation, and at rates of bias similar to the experimentally observed rates, quantitatively reproduced the experimental binding energetics. 相似文献
154.
155.
Griffin MD Dobson RC Pearce FG Antonio L Whitten AE Liew CK Mackay JP Trewhella J Jameson GB Perugini MA Gerrard JA 《Journal of molecular biology》2008,380(4):691-703
Dihydrodipicolinate synthase (DHDPS) is an essential enzyme in (S)-lysine biosynthesis and an important antibiotic target. All X-ray crystal structures solved to date reveal a homotetrameric enzyme. In order to explore the role of this quaternary structure, dimeric variants of Escherichia coli DHDPS were engineered and their properties were compared to those of the wild-type tetrameric form. X-ray crystallography reveals that the active site is not disturbed when the quaternary structure is disrupted. However, the activity of the dimeric enzymes in solution is substantially reduced, and a tetrahedral adduct of a substrate analogue is observed to be trapped at the active site in the crystal form. Remarkably, heating the dimeric enzymes increases activity. We propose that the homotetrameric structure of DHDPS reduces dynamic fluctuations present in the dimeric forms and increases specificity for the first substrate, pyruvate. By restricting motion in a key catalytic motif, a competing, non-productive reaction with a substrate analogue is avoided. Small-angle X-ray scattering and mutagenesis data, together with a B-factor analysis of the crystal structures, support this hypothesis and lead to the suggestion that in at least some cases, the evolution of quaternary enzyme structures might serve to optimise the dynamic properties of the protein subunits. 相似文献
156.
Whitten ST Wooll JO Razeghifard R García-Moreno E B Hilser VJ 《Journal of molecular biology》2001,309(5):1165-1175
Denaturant-induced unfolding is one of the most prevalent means of evaluating the structural stability of proteins and of determining the energetic consequences of mutations or changes in solution conditions. In spite of the widespread use of this approach, controversies and inconsistencies still persist with regard to the interpretation of the results of such studies. For example, most proteins show either a significant increase or a decrease (as much as 100 %) in the denaturant-dependence of the free energy of unfolding (i.e. the m-value) under increasingly acidic conditions. The pH dependence of the m-value is given different interpretations depending on whether the m-values increase or decrease with decreasing pH. In cases where m-values decrease, the decrease is attributed to the presence of an intermediate that becomes transiently stabilized during the unfolding transition at low pH. Cases where m-values increase as pH is lowered are usually interpreted in terms of an increase in the amount of surface area exposed by the denatured state at low pH. We have developed a general thermodynamic model that accounts for both types of behavior in terms of an intermediate that is populated throughout the unfolding transition. The model provides a unified framework for explaining both types of observed behavior, and the validity of the model was tested through the analysis of the pH dependence of m-values of staphylococcal nuclease. According to the model, the observed increase in m-values with decreasing pH is consistent with the existence of an intermediate that is populated during urea and guanidine unfolding. The intermediate becomes less populated during the unfolding transition at lower pH values giving rise to the apparent increase in m-values. These results argue that the prevailing interpretation need not apply to all proteins. 相似文献
157.
The pH dependence of stability of staphylococcal nuclease was studied with two independent equilibrium thermodynamic approaches. First, by measurement of stability in the pH range 9 to 3.5 by fluorescence-monitored denaturation with urea (Delta), GdnHCl (Delta), and heat (Delta). Second, by numerical integration of H(+) titration curves (Delta) measured potentiometrically under native (100 mM KCl) and unfolding (6.0 M GdnHCl) conditions. The pH dependence of stability described by Delta, Delta, and Delta was comparable but significantly different from the one described by Delta. The decrease in Delta between pH 9 and pH 4 was 4 kcal/mol greater than the decrease in Delta, Delta, and Delta in the same pH range. In 6 M GdnHCl, all the ionizable groups titrated with the pK(a) values of model compounds. Therefore, Delta represents the free energy difference between the native state (N) and an ensemble of unstructured, or expanded, and highly screened conformations. In contrast, the shallower pH dependence of stability described by Delta and by Delta between pH 9 and 5 was consistent with the titration of histidines with depressed, nativelike pK(a) values in the denatured state (D). These depressed pK(a) values likely reflect long-range electrostatic interactions with the other 29 basic groups and are a consequence of the compact character of the D state. The steep change in Delta and Delta at pH < 5 suggests that near pH 5 the structural and thermodynamic character of the D state shifts toward a state in which acidic residues titrate with normal pK(a) values, presumably because the electrostatic interactions with basic residues are lost, maybe as a consequence of an expansion. 相似文献
158.
Huang CQ Grigoriadis DE Liu Z McCarthy JR Ramphal J Webb T Whitten JP Xie MY Chen C 《Bioorganic & medicinal chemistry letters》2004,14(9):2083-2086
A series of 2-dialkylamino-4-phenylpyrimidines (7) was designed and synthesized as CRF(1) antagonists. SAR studies of this series resulted in the discovery of potent and selective antagonists 7b and 7n bearing a 4-(2,4,6-trisubstituted-phenyl) ring and a bulky 2-(N-bis(cyclopropane)methyl-N-propyl)amino group. 相似文献
159.
Vesa?P?Hyt?nen Juha?AE?M??tt? Heidi?Kidron Katrin?K?Halling Jarno?H?rh? Tuomas?Kulomaa Thomas?KM?Nyholm Mark?S?Johnson Tiina?A?Salminen Markku?S?Kulomaa Tomi?T?AirenneEmail author 《BMC biotechnology》2005,5(1):28
Background
The chicken avidin gene family consists of avidin and several avidin related genes (AVRs). Of these gene products, avidin is the best characterized and is known for its extremely high affinity for D-biotin, a property that is utilized in numerous modern life science applications. Recently, the AVR genes have been expressed as recombinant proteins, which have shown different biotin-binding properties as compared to avidin. 相似文献160.