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TitleDescriptionImage
Single molecule folding and unfolding trajectoryTrajectory of a single protein molecule folding and unfolding monitored by fluorescence resonance energy transfer from green-emitting donor dye to red-emitting acceptor dye.Enlarge
Electron microscope images of amyloid fibrilsElectron microscope images of amyloid fibrils formed by the 40-residue beta-amyloid peptide are depicted, with either "twisted" or "striated ribbon" morphologies (left). Corresponding molecular structural models, based on data from solid-state NMR and electron microscopy are shown (right).Enlarge
Custom-built apparatus for solid state NMR at low temperatures with dynamic nuclear polarization (DNP)A custom-built apparatus for solid-state NMR at low temperatures with dynamic nuclear polarization (DNP) is depicted (left). A carbon-13 NMR spectrum of an isotopically labeled peptide in frozen solution at 25 K, with and without signal enhancement from DNP is shown (right).Enlarge
Structural model for a pentameric assembly of transmembrane segments of the HIV-1 VpuproteinStructural model for a pentameric assembly of transmembrane segments of the HIV-1 Vpu protein, based on solid-state NMR and photochemical crosslinking data.Enlarge
NMR MagnetNuclear magnetic resonance magnet (9.4 Tesla = 400 MHz, wide bore).Enlarge
Low temperature MAS-DNP NMR probeA low temperature magic-angle spinning-dynamic nuclear polarization nuclear magnetic resonance probe is depicted with a cross section diagram (a) and photo of a probe head (b). The sample (shown in green) is cooled with helium while spinning at ~7 kHz.Enlarge
Dynamic Nuclear PolarizationIncrease of 13C NMR signal from melittin peptide for microwaves on (red) compared to microwaves off (black) (Journal of Magnetic Resonance, 2012)Enlarge
Single-molecule spectroscopyThis image depicts (A) the simplest kinetic scheme for FRET, (B) a schematic representation of the sequence of donor (green) and acceptor (red) photons detected after excitation by a train of laser pulses (blue), and (C) a two-dimensional histogram of FRET efficiencies (E) and relative donor lifetimes (τ∕τD) for a three-state system.Enlarge
Structures of complexes from the bacterial phosphotransferase systemEnlarge
Partially closed state of apo maltose binding proteinEnlarge
Alpha-synucleinThe protein alpha-synuclein has been implicated in the etiology of Parkinson’s disease. It rapidly exchanges between a disordered form, free in the cytosol, and a membrane-bound form, where it impacts trafficking of synaptic vesicles. Acetylation of the protein’s N-terminus plays a key role in membrane binding.Enlarge
N-terminal fusion domain of hemagglutinin, adopting a helical hairpin structure at neutral pH.Hemagglutinin is the protein that mediates entry of the influenza virus into the host cell. Its N-terminal fusion peptide cannot be seen by x-ray crystallography, but nuclear magnetic resonance reveals a remarkable alpha-helical hairpin structure (black) that embeds itself into the endosomal membrane. When the pH decreases below ca 5.5, this triggers transient opening of the hairpin into a dynamically interchanging V-shaped (red) and extended (blue) structure, while the hydrophobic sidechains (yellow) remain oriented to one surface.Enlarge
Ribbon diagram depicting the homo-dimeric catalytic core domain of the HIV1 integrase enzymeThe color coding indicates the rates at which backbone amide hydrogens exchange with solvent (blue—very slow; red—very fast), measured by nuclear magnetic resonance spectroscopy, and reports on the stability of the hydrogen bonding network.Enlarge
Structure of the Plasmodium 6-cysteine s48/s46 domainA ribbon diagram representation of the solution structure determined by nuclear magnetic resonance and a schematic diagram of the protein fold according to the structure determined.Enlarge
Comparison of clinical inhibitor binding to PR and mammalian pepsin.The image depicts three clinical inhibitors of HIV-1 PR, darunavir, amprenavir, and ritonavir, inhibit pepsin, a mammalian aspartyl protease, at low micromolar concentrations. This model based on crystal structures suggests a possible binding mode of amprenavir to pepsin. Serine residues 36 and 219 of pepsin take the place of Asp 29’ and 29 of PR.Enlarge
A natural PR variant that resembles biochemically the predominant PRM bears 20 amino acid substitutions differing markedly from those of a multi-drug resistant mutant.Sequences of natural HIV-1 PR variants (groups M, N, O, and P) are compared with an extreme drug-resistant mutant, PR20. Seven mutations (red) associated with major drug resistance are not present in the natural variants and cluster near highly conserved regions (gold) essential for enzyme functionality.Enlarge
Genotyping, chemical synthesis, and elucidation of self-cleavage of HIV-1 protease (PR) from its precursor, Gag-PolThe HIV-1 Gag-Pol polyprotein comprises the matrix, capsid, spacer peptide 1, nucleocapsid, protease, reverse transcriptase, ribonuclease, and integrase proteins (MA, CA, sp1, NC, PR, RT, RN, and IN). PR catalyzes its own release by sequential cleavages 1, 2, and 3 (upward red arrows) enabling controlled proteolysis of the Gag and Gag-Pol, indispensable for virus maturation. Cleavage 3 between the transframe region (TFR) and PR occurs intramolecularly to release a stable dimer with full catalytic activity. Subsequent cleavage at the C-terminus of PR occurs intermolecularly.Enlarge
Monomer fold and hydrophilic inhibitor of active PR dimerEach of the two identical 99-amino acid subunits of PR contributes one of the catalytic Asp25 residues. Interactions that hold the dimer together involve the active site (Asp25 residues shown) and flaps, and the β-sheet comprising the four N-terminal and four C-terminal residues of each monomer. Deletion of the C-terminal residues results in a stable but inactive PR monomer whose residues 10-90 adopt a fold similar to that of the dimer, as revealed by its NMR structure. Precursor with PR flanked by the TFR adopts a similar monomer fold. The N-terminal transframe octapeptide shown in surface representation (cleaved from the TFR at pH < 5; site 2 in figure 1) and its Glu-Asp-Leu sequence are competitive inhibitors of PR. Polar interactions with these residues enable a pH-dependent regulatory mechanism for PR maturation.Enlarge
Clinical inhibitors bind very weakly to PR precursor and to active site mutant.Active site D25N mutation decreases darunavir (DRV) binding by ~6 orders of magnitude. PRD25N dimer/DRV complex exhibitsa 3°C increase in Tm on DRV binding, compared with 22 °C for wild type PR. The precursor TFR-PR exhibits a similar low Tm because of decreased dimer stability and inhibitor affinity.Enlarge
Terminal β-sheet dimer interface of PR precursor analogueThe first crystal structures of a precursor mimetic (SFNFPR; four residues derived from the TFR are appended to its N-terminus) reveal several novel conformations, including disengagement of the four N-terminal residues (P1QIT4) from the β-sheet interface, accounting for its markedly lower dimer stability.Enlarge