Showing papers by "Chao Zhang published in 2005"

Structural bioinformatics-based design of selective, irreversible kinase inhibitors.

Abstract: The active sites of 491 human protein kinase domains are highly conserved, which makes the design of selective inhibitors a formidable challenge. We used a structural bioinformatics approach to identify two selectivity filters, a threonine and a cysteine, at defined positions in the active site of p90 ribosomal protein S6 kinase (RSK). A fluoromethylketone inhibitor, designed to exploit both selectivity filters, potently and selectively inactivated RSK1 and RSK2 in mammalian cells. Kinases with only one selectivity filter were resistant to the inhibitor, yet they became sensitized after genetic introduction of the second selectivity filter. Thus, two amino acids that distinguish RSK from other protein kinases are sufficient to confer inhibitor sensitivity.

An unbiased cell morphology-based screen for new, biologically active small molecules.

Abstract: We have implemented an unbiased cell morphology–based screen to identify small-molecule modulators of cellular processes using the Cytometrix (TM) automated imaging and analysis system. This assay format provides unbiased analysis of morphological effects induced by small molecules by capturing phenotypic readouts of most known classes of pharmacological agents and has the potential to read out pathways for which little is known. Four human-cancer cell lines and one noncancerous primary cell type were treated with 107 small molecules comprising four different protein kinase–inhibitor scaffolds. Cellular phenotypes induced by each compound were quantified by multivariate statistical analysis of the morphology, staining intensity, and spatial attributes of the cellular nuclei, microtubules, and Golgi compartments. Principal component analysis was used to identify inhibitors of cellular components not targeted by known protein kinase inhibitors. Here we focus on a hydroxyl-substituted analog (hydroxy-PP) of the known Src-family kinase inhibitor PP2 because it induced cell-specific morphological features distinct from all known kinase inhibitors in the collection. We used affinity purification to identify a target of hydroxy-PP, carbonyl reductase 1 (CBR1), a short-chain dehydrogenase-reductase. We solved the X-ray crystal structure of the CBR1/hydroxy-PP complex to 1.24 A resolution. Structure-based design of more potent and selective CBR1 inhibitors provided probes for analyzing the biological function of CBR1 in A549 cells. These studies revealed a previously unknown function for CBR1 in serum-withdrawal-induced apoptosis. Further studies indicate CBR1 inhibitors may enhance the effectiveness of anticancer anthracyclines. Morphology-based screening of diverse cancer cell types has provided a method for discovering potent new small-molecule probes for cell biological studies and anticancer drug candidates.

A family of phosphodiesterase inhibitors discovered by cocrystallography and scaffold-based drug design

Abstract: Cyclic nucleotide phosphodiesterases (PDEs) comprise a large family of enzymes that regulate a variety of cellular processes. We describe a family of potent PDE4 inhibitors discovered using an efficient method for scaffold-based drug design. This method involves an iterative approach starting with low-affinity screening of compounds followed by high-throughput cocrystallography to reveal the molecular basis underlying the activity of the newly identified compounds. Through detailed structural analysis of the interaction of the initially discovered pyrazole carboxylic ester scaffold with PDE4D using X-ray crystallography, we identified three sites of chemical substitution and designed small selective libraries of scaffold derivatives with modifications at these sites. A 4,000-fold increase in the potency of this PDE4 inhibitor was achieved after only two rounds of chemical synthesis and the structural analysis of seven pyrazole derivatives bound to PDE4B or PDE4D, revealing the robustness of this approach for identifying new inhibitors that can be further developed into drug candidates.

A second-site suppressor strategy for chemical genetic analysis of diverse protein kinases.

Abstract: Chemical genetic analysis of protein kinases involves engineering kinases to be uniquely sensitive to inhibitors and ATP analogs that are not recognized by wild-type kinases. Despite the successful application of this approach to over two dozen kinases, several kinases do not tolerate the necessary modification to the ATP binding pocket, as they lose catalytic activity or cellular function upon mutation of the 'gatekeeper' residue that governs inhibitor and nucleotide substrate specificity. Here we describe the identification of second-site suppressor mutations to rescue the activity of 'intolerant' kinases. A bacterial genetic selection for second-site suppressors using an aminoglycoside kinase APH(3')-IIIa revealed several suppressor hotspots in the kinase domain. Informed by results from this selection, we focused on the beta sheet in the N-terminal subdomain and generated a structure-based sequence alignment of protein kinases in this region. From this alignment, we identified second-site suppressors for several divergent kinases including Cdc5, MEKK1, GRK2 and Pto. The ability to identify second-site suppressors to rescue the activity of intolerant kinases should facilitate chemical genetic analysis of the majority of protein kinases in the genome.

The crystal structures of human steroidogenic factor-1 and liver receptor homologue-1.

Abstract: Steroidogenic factor-1 (SF-1) and liver receptor homologue-1 (LRH-1) belong to the fushi tarazu factor 1 subfamily of nuclear receptors. SF-1 is an essential factor for sex determination during development and regulates adrenal and gonadal steroidogenesis in the adult, whereas LRH-1 is a critical factor for development of endodermal tissues and regulates cholesterol and bile acid homeostasis. Regulatory ligands are unknown for SF-1 and LRH-1. A reported mouse LRH-1 structure revealed an empty pocket in a region commonly occupied by ligands in the structures of other nuclear receptors, and pocket-filling mutations did not alter the constitutive activity observed. Here we report the crystal structures of the putative ligand-binding domains of human SF-1 at 2.1-A resolution and human LRH-1 at 2.5-A resolution. Both structures bind a coactivator-derived peptide at the canonical activation–function surface, thus adopting the transcriptionally activating conformation. In human LRH-1, coactivator peptide binding also occurs to a second site. We discovered in both structures a phospholipid molecule bound in a pocket of the putative ligand-binding domain. MS analysis of the protein samples used for crystallization indicated that the two proteins associate with a range of phospholipids. Mutations of the pocket-lining residues reduced the transcriptional activities of SF-1 and LRH-1 in mammalian cell transfection assays without affecting their expression levels. These results suggest that human SF-1 and LRH-1 may be ligand-binding receptors, although it remains to be seen if phospholipids or possibly other molecules regulate SF-1 or LRH-1 under physiological conditions.

FastContact: rapid estimate of contact and binding free energies

Abstract: Summary: Interaction free energies are crucial for analyzing binding propensities in proteins. Although the problem of computing binding free energies remains open, approximate estimates have become very useful for filtering potential binding complexes. We report on the implementation of a fast computational estimate of the binding free energy based on a statistically determined desolvation contact potential and Coulomb electrostatics with a distance-dependent dielectric constant, and validated in the Critical Assessment of PRotein Interactions experiment. The application also reports residue contact free energies that rapidly highlight the hotspots of the interaction. Availability: The program was written in Fortran. The executable and full documentation is freely available at http://structure.pitt.edu/software/FastContact Contact: ccamacho@pitt.edu

Global mapping of the protein structure space and application in structure-based inference of protein function

Abstract: We have constructed a map of the “protein structure space” by using the pairwise structural similarity scores calculated for all nonredundant protein structures determined experimentally. As expected, proteins with similar structures clustered together in the map and the overall distribution of structural classes of this map followed closely that of the map of the “protein fold space” we have reported previously. Consequently, proteins sharing similar molecular functions also were found to colocalize in the protein structure space map, pointing toward a previously undescribed scheme for structure-based functional inference for remote homologues based on the proximity in the map of the protein structure space. We found that this scheme consistently outperformed other predictions made by using either the raw scores or normalized Z-scores of pairwise dali structure alignment.

Electronic efficiency in nanostructured thermionic and thermoelectric devices

Abstract: Advances in solid-state device design now allow the spectrum of transmitted electrons in thermionic and thermoelectric devices to be engineered in ways that were not previously possible. Here we show that the shape of the electron energy spectrum in these devices has a significant impact on their performance. We distinguish between traditional thermionic devices where electron momentum is filtered in the direction of transport only and a second type, in which the electron filtering occurs according to total electron momentum. Such ``total momentum filtered'' thermionic devices could potentially be implemented in, for example, quantum dot superlattices. It is shown that whilst total momentum filtered thermionic devices may achieve an efficiency equal to the Carnot value, traditional thermionic devices are limited to an efficiency below this. Our second main result is that the electronic efficiency of a device is not only improved by reducing the width of the transmission filter as has previously been shown, but also strongly depends on whether the transmission probability rises sharply from zero to full transmission. The benefit of increasing efficiency through a sharply rising transmission probability is that it can be achieved without sacrificing device power, in contrast to the use of a narrow transmission filter which can greatly reduce power. We show that devices that have a sharply rising transmission probability significantly outperform those that do not and that such transmission probabilities may be achieved with practical single and multibarrier devices. We discuss how the shape of the electron energy spectrum will also have an effect on the electronic efficiency of thermoelectric devices due to mathematical equivalences in the ballistic and diffusive formalisms. Finally, we present an experimental measure that might be used to provide an indication of the nature of the electron energy spectrum and the electronic efficiency of a ballistic device.

Anti-inflammatory pyrazolopyrimidines

Abstract: The present invention provides anti-inflammatory compounds useful in the treatment of diseases and conditions in which inflammation is involved in disease progression or the manifestation of symptoms of the disease or condition.

Enhanced optical transmission through metal films with rotation-symmetrical hole arrays

Abstract: The transmission of light through metal surface with subwavelength holes are influenced by many factors, and the rotational symmetry of hole arrays can be one of them. In this paper, we fabricated the hole lattices in metal films with different symmetry and measured the transmission spectra from the visible to near-infrared region. It is found that both the spectrum shape and the transmission efficiency are strongly dependent on the rotational symmetry. The spectrum shape is governed by the reciprocal vectors. And the higher is the symmetry order, the larger the peak efficiency. The results provide us with new insight into the unusual effect.

Pde4b inhibitors and uses therefor

Abstract: Compounds active on phosphodiesterase PDE4B are provided. Also provided herewith are compositions useful for treatment of PDE4B-mediated diseases or conditions, and methods for the use thereof.

The effect of zinc(II) on the growth of E . coli studied by microcalorimetry

Abstract: By using an LKB2277 Bioactivity Monitor, stop-flow mode, the power-time curves of E . coli at 37°C effected by zinc(II) were determined. Some parameters, such as growth rate constants k, inhibitory ratio I, the maximum heat production rate P max heat output Q and the time in the maximum heat production t max were obtained. According these parameters, we found that a low concentration of zinc(II) had a promoting action on the growth of E. coli, but a high concentration of zinc(II) had an inhibitory action. The toxicity of zinc(II) can also be expressed as half inhibitory concentration IC 50 of zinc(II), i.e., 50% effective in this inhibition. The value of IC 50 of zinc(II) on E. coliis 28.09 µg mL-1. The assay is quantitative, inexpensive and versatile.

Hydrographic and biological changes in the Taiwan Strait during the 1997-1998 El Niño winter

Abstract: [1] During the 1997–1998 El Nino event, the average sea surface temperature (SST) in the Taiwan Strait (TWS) in the winter was ∼1.4°C higher than that of the winter climatological mean. The areal ratio of the warm water (≥2°C above the regional mean) to the cold water (≥2°C below the regional mean) in the TWS increased by 25% while the area of the eutrophic water (chlorophyll a >1 mg m−3) was halved. Field observations also indicate that the mixed layer in the TWS became more nutrient-poor during this winter. These observations are consistent with a diminished advection of the cold and eutrophic Zhe-Min Coastal Water, and, concomitantly, an expansive intrusion of the warm and oligotrophic South China Sea Warm Current/Kuroshio Branch Water to the TWS as the northeast monsoon was weakened. Thus, El Nino events potentially can have significant ecological impacts on the TWS.

Solid-state thermionics and thermoelectrics in the ballistic transport regime

Abstract: It is shown that the equations for electrical current in solid-state thermionic and thermoelectric devices converge for devices with a width equal to the mean free path of electrons, yielding a common expression for the intensive electronic efficiency in the two types of devices. This result is used to demonstrate that the material parameters for thermionic and thermoelectric refrigerators are equal, rather than differing by a multiplicative factor as previously thought.

General Method to Construct LS Codes by Complete Complementary Sequences

Abstract: Large Area Synchronized (LAS)-CDMA, actually composed of LA codes and pulse compressing LS codes, has been proposed as a most promising scheme in 3G and 4G wireless communications. LS codes are famous for the Zero Correlation Zone (ZCZ) in the auto-correlation and cross-correlation functions, which endows the codes with the capability to perfectly reduce the Multiple Access Interference (MAI) and Inter Symbol Interference (ISI) if the maximum transmission delay is less than the length of ZCZ. In this letter, we provide a general and systematic method to construct LS codes from the set of complete complementary sequences. Our method is much more general than the ordinary LS construction method revealed previously.

Novel Sequence Pair and Set with Three Zero Correlation Windows

Abstract: In this paper, we present a set of sequence pairs which produce zero correlation windows not only in the middle part of the sum of aperiodic correlation functions, but also in the two terminal parts. We name it Ear Windows. In approximately synchronous CDMA communication system, this set of sequences is able to completely remove the inter-symbol interference (ISI) and multi-user interference (MUI) caused by the multipath effect if the maximum delay is shorter than the length of the Ear windows. In addition, it is also feasible in M-ary modulation. The intercede interference will be mitigated drastically.

Azaindoles modulating c-kit activity and uses therefor

Abstract: Compounds with 7-azaindole core structure with activity toward the receptor protein tyrosine kinase c-kit, compositions useful for treatment c-kit-mediate diseases or conditions, and methods of use thereof, are provided. Further provided are methods of c kit ligand identification and design.

Nonlinear response formula for an interacting two-dimensional electron gas under a magnetic field and microwave radiation

Abstract: Introducing a canonical transformation of the second quantized field operators for two-dimensional interacting electrons under a uniform static magnetic field and a microwave radiation field, an exact formula that transforms the retarded density response function of the electrons to that of the electrons without the radiation field is derived. The formula provides a new way to treat the effects of the microwave radiation field on the electron density response when the conventional linear response approximation is not applicable.

Principles of charge and heat transport in thermionic devices

Abstract: We enunciate the general principles that govern the transport of charge and heat in a thermionic device. We illustrate the application of these principles to the subject of domestic refrigeration. A complementary application is power generation. We distinguish Class 2 devices, in which the potential barrier on the hot side plays a role, from Class 1 devices, in which this barrier is irrelevant. We show that the effect of heat backflow is to drastically reduce the efficiency of thermionic devices in both GaAs and InSb representative semiconductor systems. We conclude that practical devices are not likely with bulk, single-barrier devices.

Ultra-toughened Al2O3–TiC–Co ceramic

Abstract: Al 2 O 3 and TiC powders in microscale have been coated with a uniform cobalt layer by electroless plating technique under application of ultrasonic wave. Co-coated Al 2 O 3 and TiC powders were then hot-pressed into Al 2 O 3 –TiC–Co ceramic by sintering at 1600 °C and 30 MPa for 30 min in vacuum. Results demonstrate that the uniformly distributed Co-phase improved the interfacial bonding of ceramic grains significantly in comparison with Al 2 O 3 –TiC (AT30) ceramic and our previous research. The fracture toughness of the new Al 2 O 3 –TiC–Co ceramic reaches the value as large as 11.28 MPa m 1/2 ; meanwhile the hardness and bending strength are greatly improved as well. The fracture surface morphology of the Al 2 O 3 –TiC–Co ceramic sample shows the characteristics of intergranular fracture.

The effect of the electron energy spectrum on electronic efficiency and power in thermionic and thermoelectric devices

Abstract: We show that the details of the energy spectrum of transmitted electrons in thermionic and thermoelectric devices have a significant impact on their performance. We distinguish between traditional thermionic devices where electron momentum is filtered in the direction of transport only and a second type, in which the electron filtering occurs according to total electron momentum. Our main result is that the electronic efficiency of a device is not only improved by reducing the width of the transmission filter, but also strongly depends on whether the transmission probability rises sharply from zero to full transmission. Finally, we comment on the implications of the effect the shape of the electron energy spectrum has on the efficiency of thermoelectric devices and suggest an experimental measure for providing insight into the nature of the electron energy spectrum.

Effects of collective excitations on the quantum well intersubband absorption

Abstract: The dependence of the intersubband absorption spectra on the Coulomb interaction and quantum well (QW) width is studied. Rather than following the Fermi–Dirac distribution, we have solved the intersubband equations of motion to determine the subband population self-consistently. We have gone beyond the linear absorption theory to show the effect of various many-body interactions on the absorption spectra. It is found that the redistribution of electrons in excited states reduces the absorption. Our results indicate that the line shape and peak position are determined by the interplay of different collective excitations, such as the Fermi edge singularity and the intersubband plasmon. The dependence of the absorption spectrum on the QW width and the subband effective masses is also discussed.

Two Dimensional Combined Complementary Sequence and Its Application in Multi-Carrier CDMA

Abstract: Multi-Carrier CDMA (MC-CDMA) has been considered as a combination of the techniques of Code Division Multiple Access (CDMA) and Orthogonal Frequency Division Multiplex (OFDM). However, even until now, the efficient MC-CDMA scheme is still under study because of the inherent bugs in OFDM, such as the troubles caused by Multiple Access Interference (MAI) and Peak to Average Power Ratio (PAPR). In this paper, we present a novel two-dimensional spreading sequence named Two Dimensional Combined Complementary Sequence (TDC). If we take this kind of sequences as spreading codes, several prominent advantages can be achieved compared with traditional MC-CDMA. First, it can achieve MAI free in the multi-path transmission both in uplink and downlink. Second, it offers low PAPR value within 3 dB with a quite simple architecture. The last but not the least, the proposed MC-CDMA scheme turns out to be an efficient approach with high bandwidth efficiency, high spreading efficiency and flexible transmission rate enriched by a special shift-and-add modulation. Meanwhile, an algorithm that constructs TDC sequences is discussed in details. Based on above results, we can get the conclusion that the novel TDC sequences and corresponding MC-CDMA architecture have great potential for applications in next generation wireless mobile communications, which require high transmission rate in hostile and complicated channels.