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We thank T. Kortemme (UCSF) and members of the Sali laboratory for valuable comments and suggestions. We are also grateful for the support of the U.S. ... This difference occurs because life cycle annotation is available for 1930 (10%) of T. cruzi proteins but only 120 (1%) of T. brucei proteins (Supplemental Table S3 ). ... The method recovered 67% (n ¼ 2) of the known T. brucei-human interactions. ...doi:10.1110/ps.073228407 pmid:17965183 pmcid:PMC2222825 fatcat:trhw4zvo7vedpc2khxx3yufhzq
Disulfide-rich peptides (DRPs) are found throughout nature. They are suitable scaffolds for drug development due to their small cores, whose disulfide bonds impart extraordinary chemical and biological stability. A challenge in developing a DRP therapeutic is to engineer binding to a specific target. This challenge can be overcome by (i) sampling the large sequence space of a given scaffold through a phage display library and by (ii) panning multiple libraries encoding structurally distinctdoi:10.1186/s12859-016-1350-9 pmid:27881076 pmcid:PMC5120537 fatcat:jloxdqcsgfdzdgdmer7x2opnq4
more »... folds. Here, we implement a protocol for defining these diverse scaffolds, based on clustering structurally defined DRPs according to their conformational similarity. Results: We developed and applied a hierarchical clustering protocol based on DRP structural similarity, followed by two post-processing steps, to classify 806 unique DRP structures into 81 clusters. The 20 most populated clusters comprised 85% of all DRPs. Representative scaffolds were selected from each of these clusters; the representatives were structurally distinct from one another, but similar to other DRPs in their respective clusters. To demonstrate the utility of the clusters, phage libraries were constructed for three of the representative scaffolds and panned against interleukin-23. One library produced a peptide that bound to this target with an IC 50 of 3.3 μM. Conclusions: Most DRP clusters contained members that were diverse in sequence, host organism, and interacting proteins, indicating that cluster members were functionally diverse despite having similar structure. Only 20 peptide scaffolds accounted for most of the natural DRP structural diversity, providing suitable starting points for seeding phage display experiments. Through selection of the scaffold surface to vary in phage display, libraries can be designed that present sequence diversity in architecturally distinct, biologically relevant combinations of secondary structures. We supported this hypothesis with a proof-of-concept experiment in which three phage libraries were constructed and panned against the IL-23 target, resulting in a single-digit μM hit and suggesting that a collection of libraries based on the full set of 20 scaffolds increases the potential to identify efficiently peptide binders to a protein target in a drug discovery program.
The effects of single mutations on proteinligand interactions were predicted by calculating the binding affinity changes using PremPLI (https://lilab.jysw.suda.edu.cn/research/PremPLI/) (Sun, T., Chen ...doi:10.1101/2022.01.26.477860 fatcat:q3aa447m4nbgxeupsoik4uw4je
For a solved structure or a comparative model, the DSSP program was used to assess secondary structure (mapping results "H", "G", and "I" to α-helix, "B" and "E" to β-sheet, and "S", "T", "L" to loop) ... DT Barkan, DR Hostetter et al ...doi:10.1093/bioinformatics/btq267 pmid:20505003 pmcid:PMC2894511 fatcat:3ji5tts7ajhhzoxg5lyas2nsl4
The nearly 600 proteases in the human genome regulate a diversity of biological processes, including programmed cell death. Comprehensive characterization of protease signaling in complex biological samples is limited by available proteomic methods. We have developed a general approach for global identification of proteolytic cleavage sites using an engineered enzyme to selectively biotinylate free protein N termini for positive enrichment of corresponding N-terminal peptides. Using this methoddoi:10.1016/j.cell.2008.08.012 pmid:18722006 pmcid:PMC2566540 fatcat:onaagos6djdd7oa6r6abj3lzem
more »... to study apoptosis, we have sequenced 333 caspase-like cleavage sites distributed among 292 protein substrates. These sites are generally not predicted by in vitro caspase substrate specificity but can be used to predict other physiological caspase cleavage sites. Structural bioinformatic studies show that caspase cleavage sites often appear in surfaceaccessible loops and even occasionally in helical regions. Strikingly, we also find that a disproportionate number of caspase substrates physically interact, suggesting that these dimeric proteases target protein complexes and networks to elicit apoptosis.
Citation: Pandey KC, Barkan DT, Sali A, Rosenthal PJ (2009) Regulatory Elements within the Prodomain of Falcipain-2, a Cysteine Protease of the Malaria Parasite Plasmodium falciparum. ...doi:10.1371/journal.pone.0005694 pmid:19479029 pmcid:PMC2682653 fatcat:dx7cd4h32rgx7owi33fkhv2tse
Present Design Concept Related to the Design Requirements tfJEOUHEMENT FEATURES \ MINIMUM RADIATION 1£NGTH THERMAL DISSIPATION POSITIONAL ACCURACY EASE OF ASSEMBLY MAINTENANCE COVERAGE T\ ...doi:10.1007/978-1-4615-3746-5_88 fatcat:pfdatasedvfhbd5srhjsdfzvbm
PTM Sequence Motifs-Previous analyses, based on a significantly smaller scale O-GlcNAcylated peptide data set, suggested a PVXS/T motif for substrates of OGT (18) . ... "S" designates small/nonpolar (A, G, S, T); "A" designates acidic (D, E); "B" designates basic (H, K, R); "H" designates hydrophobic (C, R, I, L, M, P, V, W); and "P" designates polar (N, Q, Y). ...doi:10.1074/mcp.o112.018366 pmid:22645316 pmcid:PMC3412957 fatcat:6eeypg3ejjbwdozeuusypzczru
AbstractCoronaviruses, as exemplified by SARS-CoV-2, can evolve and spread rapidly to cause severe disease morbidity and mortality. Direct acting antivirals (DAAs) are highly effective in decreasing disease burden especially when they target essential viral enzymes, such as proteases and polymerases, as demonstrated in HIV-1 and HCV and most recently SARS-CoV-2. Optimization of these DAAs through iterative structure-based drug design has been shown to be critical. Particularly, thedoi:10.1101/2022.01.25.477757 fatcat:w6x2c5kpc5hixdbumaz3avk3mu
more »... y conserved molecular mechanisms underlying viral replication can be leveraged to develop robust antivirals against rapidly evolving viral targets. The main protease (Mpro) of SARS-CoV-2, which is evolutionarily constrained to recognize and cleave 11 specific sites to promote viral maturation, exemplifies one such target. In this study we define the substrate envelope of Mpro by determining the molecular basis of substrate recognition, through nine high-resolution cocrystal structures of SARS-CoV-2 Mpro with the viral cleavage sites. These structures enable identification of evolutionarily vulnerable sites beyond the substrate envelope that may be susceptible to drug resistance and compromise binding of the newly developed Mpro inhibitors.
Journal of Virology
Data were first normalized to background amplification in the respective no-template control (ΔC T ) before comparing nonenriched versus enriched samples (ΔΔC T ). ... Target enrichment relies on using HBV-specific probes Actin TSS TAG AAG TCG CAG GAC CAC ACT NA TGG GTA GGT TTG TAG CCT TCA T NA Nanog TSS TGG GTT TGT CTT CAG GTT CTG NA CTA CTG ACC CAC CCT TGT ...doi:10.1128/jvi.02036-18 pmid:30787147 pmcid:PMC6475771 fatcat:va5h6nt4rvdshdeh6upp3dgiwy
Lin, David T. Barkan, Claudio Ciferri, Andrea Carfì, Tahmineh Akbarnejad Yazdi, Peter Skewes-Cox, Brigitte Wiedmann, Nadine Jarousse, Weidong Zhong, Adam Feire, and Christy M. ...doi:10.1128/aac.00382-16 pmid:27270290 pmcid:PMC4958183 fatcat:nfhcvitktreodcmihvxlssvhci
The monobactam scaffold is attractive for the development of new agents to treat infections caused by drug-resistant Gram-negative bacteria since it is stable to metallo-β-lactamases (MBLs). However, the clinically used monobactam aztreonam lacks stability to serine β-lactamases (SBLs) that are often co-expressed with MBLs. LYS228 is stable to MBLs and most SBLs. LYS228 bound purified Escherichia coli penicillin binding protein 3 (PBP3) similarly to aztreonam (k2/Kd = 367504 s-1M-1 and 409229doi:10.1128/aac.01200-18 pmid:30061293 fatcat:ikaaf27frbbg7pampgecztfwmm
more »... 1M-1, respectively) according to stopped-flow fluorimetry. A gel-based assay showed that LYS228 bound mainly to E. coli PBP3, with weaker binding to PBP1a and PBP1b. Exposing E. coli cells to LYS228 caused filamentation, consistent with impaired cell division. No single-step mutants were selected from twelve Enterobacteriaceae strains expressing different classes of β-lactamases at 8X the minimum inhibitory concentration (MIC) of LYS228 (frequency <2.5x10-9). At 4X the MIC, mutants were selected from two of twelve strains at frequencies of 1.8x10-7 and 4.2x10-9. LYS228 MICs were ≤ 2 μg/mL against all mutants. These frequencies compared favorably to those for meropenem and tigecycline. Mutations decreasing LYS228 susceptibility occurred in ramR and cpxA (Klebsiella pneumoniae) and baeS (E. coli and K. pneumoniae). Susceptibility of E. coli ATCC 25922 to LYS228 decreased 256-fold (MIC 0.125 to 32 μg/mL) after 20 serial passages. Mutants accumulated mutations in ftsI (encoding the target, PBP3), baeR, acrD, envZ, sucB and rfaI. These results support the continued development of LYS228, which is currently undergoing Phase II clinical trials for complicated intraabdominal infection and complicated urinary tract infection (https://clinicaltrials.gov/ct2/show/NCT03377426; https://clinicaltrials.gov/ct2/show/NCT03354754).
Barkan, O., and Barkan, H.: Central and Paracentral Homonymous Hemianopic Scotomas, Am. J. Ophth. 13:853-858, 1930. Barkan, O., and Boyle, S. T.: Paracentral Homonymous Hemianopic Scotoma, Arch. ... *° Bollack, David and Puech ** and Vail.?’ Central Scotomas from Mechanical Forces. ...
National Union Catalog
fau- orse. au- ew 15° ole- 94° on, 6* 1 Library of Congress Author Catalog Barish, David T Acoustical airspeed indicators. Pasadena, 1950. 371. Hius, 2em, Thesis-—+ ag tia area roe of Technology. ... TL589.2.A5B29 629.13515 52-16322 Barish, David T Barjavel, René, 1911- Le voyageur imprudent, roman extraordinaire. Paris, ia ae iy L ere ay PQ2603.A435V6 50-52532 Barjonet, André. ...
Appoint Hans Barkan to succeed J. W. Jervey, deceased. & Committee on American Orthoptic Council: Truman L. Roves, Lawrence T. Post, George S. Campion. 9. ... Kron- ield, Chicago, and Otto Barkan, San Francisco. Drs. Paul A. Chandler and Carl C. ...
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