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The modern biopharmaceutical industry traces its roots to the dawn of the twentieth century, coincident with marketing of aspirin--a signature event in the history of modern drug development. Although the archetypal discovery process did not change markedly in the first seven decades of the industry, the past fifty years have seen two successive waves of transformative innovation in the development of drug molecules: the rise of 'rational drug discovery' methodology in the 1970s, followed by the invention of recombinant protein-based therapeutic agents in the 1980s. An incipient fourth wave is the advent of multispecific drugs. The successful development of prospectively designed multispecific drugs has the potential to reconfigure our ideas of how target-based therapeutic molecules can work, and what it is possible to achieve with them. Here I review the two major classes of multispecific drugs: those that enrich a therapeutic agent at a particular site of action and those that link a therapeutic target to a biological effector. The latter class--being freed from the constraint of having to directly modulate the target upon binding--may enable access to components of the proteome that currently cannot be targeted by drugs. The development and future prospects of prospectively designed multispecific drugs, which have the potential to transform the biopharmaceutical industry by enabling the targeting of currently inaccessible components of the proteome, are reviewed., Author(s): Raymond J. Deshaies [sup.1] Author Affiliations: (1) Amgen Research, Thousand Oaks, USA Main Since the 1970s, discovery and development of therapeutic agents has been dominated by rational drug discovery[sup.1] [...]

A process termed ubiquitination mediates the regulated destruction of cellular proteins, thereby preventing disease or infection. Structural data now reveal how a crucial regulator of ubiquitination enzymes coordinates this process. Structural data reveal a key step that regulates protein degradation., Author(s): Raymond J. Deshaies, Nathan W. Pierce Author Affiliations: Transfer of ubiquitin protein caught in the act Many cellular functions that occur in eukaryotes (organisms whose cells contain a nucleus) [...]

Ribosomal surveillance pathways scan for ribosomes that are transiently paused or terminally stalled owing to structural elements in mRNAs or nascent chain sequences.sup.1, 2. Some stalls in budding yeast are sensed by the GTPase Hbs1, which loads Dom34, a catalytically inactive member of the archaeo-eukaryotic release factor 1 superfamily. Hbs1-Dom34 and the ATPase Rli1 dissociate stalled ribosomes into 40S and 60S subunits. However, the 60S subunits retain the peptidyl-tRNA nascent chains, which recruit the ribosome quality control complex that consists of Rqc1-Rqc2-Ltn1-Cdc48-Ufd1-Npl4. Nascent chains ubiquitylated by the E3 ubiquitin ligase Ltn1 are extracted from the 60S subunit by the ATPase Cdc48-Ufd1-Npl4 and presented to the 26S proteasome for degradation.sup.3-9. Failure to degrade the nascent chains leads to protein aggregation and proteotoxic stress in yeast and neurodegeneration in mice.sup.10-14. Despite intensive investigations on the ribosome quality control pathway, it is not known how the tRNA is hydrolysed from the ubiquitylated nascent chain before its degradation. Here we show that the Cdc48 adaptor Vms1 is a peptidyl-tRNA hydrolase. Similar to classical eukaryotic release factor 1, Vms1 activity is dependent on a conserved catalytic glutamine. Evolutionary analysis indicates that yeast Vms1 is the founding member of a clade of eukaryotic release factor 1 homologues that we designate the Vms1-like release factor 1 clade.The Cdc48 adaptor Vms1 is a peptidyl-tRNA hydrolase that cooperates with the ribosome quality control complex to catalyse the removal of nascent polypeptides from stalled ribosomes., Author(s): Rati Verma [sup.1] [sup.2] [sup.3] , Kurt M. Reichermeier [sup.2] [sup.5] , A. Maxwell Burroughs [sup.4] , Robert S. Oania [sup.1] [sup.2] , Justin M. Reitsma [sup.2] , L. [...]

The pathway by which ubiquitin chains are generated on substrate through a cascade of enzymes consisting of an E1, E2 and E3 remains unclear. Multiple distinct models involving chain assembly on E2 or substrate have been proposed. However, the speed and complexity of the reaction have precluded direct experimental tests to distinguish between potential pathways. Here we introduce new theoretical and experimental methodologies to address both limitations. A quantitative framework based on product distribution predicts that the really interesting new gene (RING) E3 enzymes [SCF.sup.Cdc4] and [SCF.sup.β-TrCP] work with the E2 Cdc34 to build polyubiquitin chains on substrates by sequential transfers of single ubiquitins. Measurements with millisecond time resolution directly demonstrate that substrate polyubiquitylation proceeds sequentially. Our results present an unprecedented glimpse into the mechanism of RING ubiquitin ligases and illuminate the quantitative parameters that underlie the rate and pattern of ubiquitin chain assembly., Attachment of a polyubiquitin chain with at least four ubiquitins linked together through their lysine 48 residue (Lys 48) targets proteins to the proteasome for degradation (1). A cascade of [...]

Author(s): J. Russell Lipford [1]; Geoffrey T. Smith [1]; Yong Chi [1, 2]; Raymond J. Deshaies (corresponding author) [1] The ubiquitin-proteasome system (UPS) promotes the destruction of target proteins by [...]

The crystal structure of the COP9 signalosome, a large protein complex that regulates intracellular protein degradation, reveals how the complex achieves exquisite specificity for its substrates. Some 20 years ago [...]

Drug discovery is hard. Even harder is drug discovery aimed at biological systems that haven't previously been tested as therapeutic targets. The extraordinary challenge is brought home with sobering clarity [...]