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Journal Issue - Volume 7 Issue 11 (November 1998)

Abstract The rate constants for the processes that lead to local opening and closing of the structures around hydrogen bonds in native proteins have been determined for most of the secondary structure hydrogen bonds in the four‐helix protein acyl coenzyme A binding protein. In an analysis that combines these results with the energies of activation of the opening processes and the stability of the local structures, three groups of...

Abstract Mitogen‐activated protein (MAP) kinases are serine/threonine kinases that mediate intracellular signal transduction pathways.Pyridinyl imidazole compounds block pro‐inflammatory cytokine production and are specific p38 kinase inhibitors. ERK2 is related to p38 in sequence and structure, but is not inhibited by pyridinyl imidazole inhibitors. Crystal structures of two pyridinyl imidazoles complexed with p38 revealed these...

Abstract Two cytotoxic proteins, bovine pancreatic ribonuclease A (RNase A), and a restriction endonuclease from Haemophilus parainfluenzae (HpaI), were produced using a novel semisynthetic approach that utilizes a protein splicing element, an intein, to generate a reactive thioester at the C‐terminus of a recombinant protein. Nucleophilic attack on this thioester by the N‐terminal cysteine of a synthetic peptide ultimately leads to the...

Abstract Retroviral nucleocapsid proteins (NCPs) are CCHC‐type zinc finger proteins that mediate virion RNA binding activities associated with retrovirus assembly and genomic RNA encapsidation. Mason‐Pfizer monkey virus (MPMV), a type D retrovirus, encodes a 96‐amino acid nucleocapsid protein, which contains two Cys‐X2‐Cys‐X4‐His‐X4‐Cys (CCHC) zinc fingers connected by an unusually long 15‐amino acid linker. Homonuclear,...

  • Solution structures of stromelysin complexed to thiadiazole inhibitors

  • Brian J. Stockman, Daniel J. Waldon, Jo A. Gates, Terrence A. Scahill, David A. Kloosterman, Stephen A. Mizsak, E. Jon Jacobsen, Kenneth L. Belonga, Mark A. Mitchell, Boryeu Mao, James D. Petke, Linda Goodman, Elaine A. Powers, Steven R. Ledbetter, Paul S. Kaytes, Gabriel Vogeli, Vincent P. Marshall, Gary L. Petzold, Roger A. Poorman
  • Published in Wiley Interscience on Dec 31, 2008
  • DOI: 10.1002/pro.5560071105 (p 2281-2286)

Abstract Unregulated or overexpressed matrix metalloproteinases (MMPs), including stromelysin, collagenase, and gelatinase, have been implicated in several pathological conditions including arthritis and cancer. Small‐molecule MMP inhibitors may have therapeutic value in the treatment of these diseases. In this regard, the solution structures of two stromelysin/inhibitor complexes have been investigated using H, 13C, and 15N NMR...

Abstract Antiparallel β‐sheets present two distinct environments to inter‐strand residue pairs: βA, HB sites have two backbone hydrogen bonds; whereas at βA, NHB positions backbone hydrogen bonding is precluded. We used statistical methods to compare the frequencies of amino acid pairs at each site. Only ˜ 10% of the 210 possible pairs showed occupancies that differed significantly between the two sites. Trends were clear in the...

Abstract We investigated the pathway for pressure unfolding of metmyoglobin using molecular dynamics (MD) for a range of pressures (0. 1 MPa to 1. 2 GPa) and a temperature of 300 K. We find that the unfolding of metmyoglobin proceeds via a two‐step mechanism native → molten globule intermediate → unfolded, where the molten globule forms at 700 MPa. The simulation describes qualitatively the experimental behavior of metmyoglobin...

Abstract One of the major problems encountered in antiviral therapy against AIDS is the emergence of viral variants that exhibit drug resistance. The sequences of proteases (PRs) from related retroviruses sometimes include, at structurally equivalent positions, amino acids identical to those found in drug‐resistant forms of HIV‐1 PR. The statine‐based inhibitor LP‐130 was found to be a universal, nanomolar‐range inhibitor against...

Abstract Protein ß‐sheets can be regarded as surfaces. Two surfaces can be connected along a common edge to form a larger surface, or two edges of a surface can coalesce to form a closed sheet such as a ß‐barrel. Singular points are locations where these connections are not perfect. In protein ß‐sheets, a singular point is characterized by a residue separating two ß‐ladders. In this paper, we study the singular points of protein...

Abstract A flavodoxin from Azotobacter vinelandii is chosen as a model system to study the folding of α/ß doubly wound proteins. The guanidinium hydrochloride induced unfolding of apoflavodoxin is demonstrated to be reversible. Apoflavodoxin thus can fold in the absence of the FMN cofactor. The unfolding curves obtained for wild‐type, C69A and C69S apoflavodoxin as monitored by circular dichroism and fluorescence spectroscopy do not...

Abstract We have devised a procedure using monovalent phage display to select for stable mutants in the pro‐domain of the serine protease, subtilisin BPN'. In complex with subtilisin, the pro‐domain assumes a compact structure with a four‐stranded antiparallel β‐sheet and two three‐turn α‐helices. When isolated, however, the pro‐domain is 97% unfolded. These experiments use combinatorial mutagenesis to select for stabilizing amino...

Abstract We have expressed and characterized a mutant of Xenopus laevis Cu, Zn superoxide dismutase in which four highly conserved charged residues belonging to the electrostatic loop have been replaced by neutral side chains: Lys120 → Leu, Asp130 → Gln, Glu131 → Gln, and Lys134 → Thr. At low ionic strength, the mutant enzyme is one of the fastest superoxide dismutases ever assayed (k = 6. 7 × 109 M−1 s−1, at pH 7 and μ = 0. 02 M). Brownian...

Abstract Influenza virus hemagglutinin (HA) has served as a paradigm for both pH‐dependent and ‐independent viral membrane fusion. Although large conformational changes were observed by X‐ray crystallography when soluble fragments of HA were subjected to fusion‐pH conditions, it is not clear whether the same changes occur in membrane‐bound HA, what the spatial relationship is between the conformationally changed HA and the target...

Abstract An increasing number of experimental and theoretical studies have demonstrated the importance of the 310‐helix/α‐helix/coil equilibrium for the structure and folding of peptides and proteins. One way to perturb this equilibrium is to introduce side‐chain interactions that stabilize or destabilize one helix. For example, an attractive i, i + 4 interaction, present only in the α‐helix, will favor the α‐helix over 310, while an i, i + 4...

Abstract The chaperone protein SecB is dedicated to the facilitation of export of proteins from the cytoplasm to the periplasm and outer membrane of Escherichia coli. It functions to bind and deliver precursors of exported proteins to the membrane‐associated translocation apparatus before the precursors fold into their native stable structures. The binding to SecB is characterized by a high selectivity for ligands having nonnative...

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