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Tsai Y.,SLAC | Tsai Y.,Stanford University | McPhillips S.E.,SLAC | Gonzalez A.,SLAC | And 13 more authors.
Acta Crystallographica Section D: Biological Crystallography | Year: 2013

AutoDrug is software based upon the scientific workflow paradigm that integrates the Stanford Synchrotron Radiation Lightsource macromolecular crystallography beamlines and third-party processing software to automate the crystallography steps of the fragment-based drug-discovery process. AutoDrug screens a cassette of fragment-soaked crystals, selects crystals for data collection based on screening results and user-specified criteria and determines optimal data-collection strategies. It then collects and processes diffraction data, performs molecular replacement using provided models and detects electron density that is likely to arise from bound fragments. All processes are fully automated, i.e. are performed without user interaction or supervision. Samples can be screened in groups corresponding to particular proteins, crystal forms and/or soaking conditions. A single AutoDrug run is only limited by the capacity of the sample-storage dewar at the beamline: currently 288 samples. AutoDrug was developed in conjunction with RestFlow, a new scientific workflow-automation framework. RestFlow simplifies the design of AutoDrug by managing the flow of data and the organization of results and by orchestrating the execution of computational pipeline steps. It also simplifies the execution and interaction of third-party programs and the beamline-control system. Modeling AutoDrug as a scientific workflow enables multiple variants that meet the requirements of different user groups to be developed and supported. A workflow tailored to mimic the crystallography stages comprising the drug-discovery pipeline of CoCrystal Discovery Inc. has been deployed and successfully demonstrated. This workflow was run once on the same 96 samples that the group had examined manually and the workflow cycled successfully through all of the samples, collected data from the same samples that were selected manually and located the same peaks of unmodeled density in the resulting difference Fourier maps. © 2013 International Union of Crystallography Printed in Singapore - all rights reserved.


Colussi T.M.,University of Colorado at Denver | Colussi T.M.,Howard Hughes Medical Institute | Colussi T.M.,Northeastern University | Costantino D.A.,University of Colorado at Denver | And 12 more authors.
Nature | Year: 2015

The central dogma of gene expression (DNA to RNA to protein) is universal, but in different domains of life there are fundamental mechanistic differences within this pathway. For example, the canonical molecular signals used to initiate protein synthesis in bacteria and eukaryotes are mutually exclusive. However, the core structures and conformational dynamics of ribosomes that are responsible for the translation steps that take place after initiation are ancient and conserved across the domains of life. We wanted to explore whether an undiscovered RNA-based signal might be able to use these conserved features, bypassing mechanisms specific to each domain of life, and initiate protein synthesis in both bacteria and eukaryotes. Although structured internal ribosome entry site (IRES) RNAs can manipulate ribosomes to initiate translation in eukaryotic cells, an analogous RNA structure-based mechanism has not been observed in bacteria. Here we report our discovery that a eukaryotic viral IRES can initiate translation in live bacteria. We solved the crystal structure of this IRES bound to a bacterial ribosome to 3.8 Å resolution, revealing that despite differences between bacterial and eukaryotic ribosomes this IRES binds directly to both and occupies the space normally used by transfer RNAs. Initiation in both bacteria and eukaryotes depends on the structure of the IRES RNA, but in bacteria this RNA uses a different mechanism that includes a form of ribosome repositioning after initial recruitment. This IRES RNA bridges billions of years of evolutionary divergence and provides an example of an RNA structure-based translation initiation signal capable of operating in two domains of life. © 2015 Macmillan Publishers Limited.


Gong P.,Colorado State University | Gong P.,CAS Wuhan Institute of Virology | Kortus M.G.,Colorado State University | Nix J.C.,Lawrence Berkeley National Laboratory | And 2 more authors.
PLoS ONE | Year: 2013

RNA-dependent RNA polymerases play a vital role in the growth of RNA viruses where they are responsible for genome replication, but do so with rather low fidelity that allows for the rapid adaptation to different host cell environments. These polymerases are also a target for antiviral drug development. However, both drug discovery efforts and our understanding of fidelity determinants have been hampered by a lack of detailed structural information about functional polymerase-RNA complexes and the structural changes that take place during the elongation cycle. Many of the molecular details associated with nucleotide selection and catalysis were revealed in our recent structure of the poliovirus polymerase-RNA complex solved by first purifying and then crystallizing stalled elongation complexes. In the work presented here we extend that basic methodology to determine nine new structures of poliovirus, coxsackievirus, and rhinovirus elongation complexes at 2.2-2.9 Å resolution. The structures highlight conserved features of picornaviral polymerases and the interactions they make with the template and product RNA strands, including a tight grip on eight basepairs of the nascent duplex, a fully pre-positioned templating nucleotide, and a conserved binding pocket for the +2 position template strand base. At the active site we see a pre-bound magnesium ion and there is conservation of a non-standard backbone conformation of the template strand in an interaction that may aid in triggering RNA translocation via contact with the conserved polymerase motif B. Moreover, by engineering plasticity into RNA-RNA contacts, we obtain crystal forms that are capable of multiple rounds of in-crystal catalysis and RNA translocation. Together, the data demonstrate that engineering flexible RNA contacts to promote crystal lattice formation is a versatile platform that can be used to solve the structures of viral RdRP elongation complexes and their catalytic cycle intermediates. © 2013 Gong et al.


Chu M.L.-H.,Stanford University | Ahn V.E.,Stanford University | Ahn V.E.,Cocrystal Discovery Inc. | Choi H.-J.,Stanford University | And 4 more authors.
Structure | Year: 2013

Wnts are secreted growth factors that have critical roles in cell fate determination and stem cell renewal. The Wnt/β-catenin pathway is initiated by binding of a Wnt protein to a Frizzled (Fzd) receptor and a coreceptor, LDL receptor-related protein 5 or 6 (LRP5/6). We report the 2.1 Å resolution crystal structure of a Drosophila WntD fragment encompassing the N-terminal domain and the linker that connects it to the C-terminal domain. Differences in the structures of WntD and Xenopus Wnt8, including the positions of a receptor-binding β hairpin and a large solvent-filled cavity in the helical core, indicate conformational plasticity in the N-terminal domain that may be important for Wnt-Frizzled specificity. Structure-based mutational analysis of mouse Wnt3a shows that the linker between the N- and C-terminal domains is required for LRP6 binding. These findings provide important insights into Wnt function and evolution. © 2013 Elsevier Ltd.


Santos N.,University of California at Santa Cruz | Zhu J.,University of California at Santa Cruz | Zhu J.,Cocrystal Discovery Inc. | Donohue J.P.,University of California at Santa Cruz | And 2 more authors.
Structure | Year: 2013

Bacterial translation termination is mediated by release factors RF1 and RF2, which recognize stop codons and catalyze hydrolysis of the peptidyl-tRNA ester bond. The catalytic mechanism has been debated. We proposed that the backbone amide NH group, rather than the side chain, of the glutamine of the universally conserved GGQ motif participates in catalysis by H-bonding to the tetrahedral transition-state intermediate and by product stabilization. This was supported by complete loss of RF1 catalytic activity when glutamine is replaced by proline, the only residue that lacks a backbone NH group. Here, we present the 3.4 Å crystal structure of the ribosome complex containing the RF2 Q253P mutant and find that its fold, including the GGP sequence, is virtually identical to that of wild-type RF2. This rules out proline-induced misfolding and further supports the proposal that catalytic activity requires interaction of the Gln-253 backbone amide with the 3′ end of peptidyl-tRNA. © 2013 Elsevier Ltd.


Patent
Cocrystal Discovery Inc. | Date: 2011-12-16

The present invention provides, among other things, compounds represented by the general Formula I: and pharmaceutically acceptable salts thereof, wherein X, Y, R^(1A), R^(1B), R^(2), and R^(3 )are as defined in classes and subclasses herein and compositions (e.g., pharmaceutical compositions) comprising such compounds, which compounds are useful as inhibitors of hepatitis C virus polymerase, and thus are useful, for example, as medicaments for the treatment of HCV infection.


Patent
Cocrystal Discovery Inc. | Date: 2013-06-20

The present invention provides, among other things, compounds represented by the general Formula I: and pharmaceutically acceptable salts thereof, wherein X, Y, R^(2), and R^(3 )are as defined in classes and subclasses herein and compositions (e.g., pharmaceutical compositions) comprising such compounds, which compounds are useful as inhibitors of hepatitis C virus polymerase, and thus are useful, for example, as medicaments for the treatment of HCV infection.


Patent
Cocrystal Discovery Inc. | Date: 2014-07-08

The present invention provides, among other things, compounds represented by the general Formula I: and pharmaceutically acceptable salts thereof, wherein X, Y, R^(1A), R^(1B), R^(2), and R^(3 )are as defined in classes and subclasses herein and compositions (e.g., pharmaceutical compositions) comprising such compounds, which compounds are useful as inhibitors of hepatitis C virus polymerase, and thus are useful, for example, as medicaments for the treatment of HCV infection.


Archus Orthopedics Angles For a Deal, Alder Takes on Roche, Cocrystal Raises $10 Million, & More Seattle-Area Life Sciences News There wasn’t a lot of headline news in Seattle biotech in the last week, but we found several interesting features that offer previews of what’s coming in the worlds of new drugs and devices. –I learned about a small nonprofit in the Tri-Cities that has come up with a simple, elegant way to fix broken bones in the developing world without using expensive equipment. The organization, called Sign, has caught the eye of Seattle-based PATH, the global health organization, which has ideas for bringing this idea to the world stage. –Medical device companies often fly below the radar, and we found one in our backyard that is developing artificial spine implants. Archus Orthopedics could do for the spine what orthopedists have been doing for years with modern hip and knee replacements. –The former No. 2 executive at Icos, Gary Wilcox, re-emerged on the biotech scene last week in a big way, as chairman and CEO of Cocrystal Discovery, an antiviral drugmaker that has raised $10 million from an investment fund led by billionaire entrepreneur Phillip Frost. Memorable quote from the 61-year-old Wilcox: “I feel like I’m 21 again.” –I sat down with Lee Huntsman, the director of Washington’s Life Sciences Discovery Fund for an in-depth interview about how this 10-year, $350 million program intends to make an impact on the local biotech sector. Readers are free to draw their own conclusions, but here’s his take on why Washington’s approach stacks up fairly well with the big boys from California and Massachusetts. –Alder Biopharmaceuticals gave me the inside scoop on how it plans to take on Roche with a “fast-follower” antibody drug for rheumatoid arthritis. It’s an exciting time at Alder—we’ll know within a year if this drug is a serious threat to one of the world’s biggest pharma players.

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