Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
329
result(s) for
"Shaffer, Paul"
Sort by:
We'll be here for the rest of our lives : a swingin' show-biz saga
In this candid memoir--in which he dishes on everyone from John Belushi and Jerry Lewis to Mel Gibson and Britney Spears--Paul Shaffer gives readers the full behind-the-scenes story of his life, from banging out pop tunes on the piano at the age of twelve to leading the band every night at the Sullivan Theater.
Book
Crystal structure of human glycine receptor-α3 bound to antagonist strychnine
The X-ray crystal structure of the human glycine receptor in the presence of strychnine, an antagonist, reveals how antagonist binding leads to closure of the channel pore.
Structure of human GlyR
The strychnine-sensitive glycine receptor (GlyR) mediates neurotransmission throughout the spinal cord and brainstem. These ligand-gated channels control a wide range of motor and sensory functions, including vision and audition, and their dysfunction is linked to multiple neurological disorders, including autism and hyperekplexia. In this manuscript, the authors report the X-ray crystal structure of human GlyR in the presence of the antagonist strychnine. The structure reveals how antagonist binding leads to closure of the channel pore. Also in this issue of
Nature
, Eric Gouaux and colleagues have determined the high-resolution electron cryo-microscopy structure of strychnine-sensitive glycine receptor (GlyR) from zebrafish in both agonist- and antagonist-bound forms.
Neurotransmitter-gated ion channels of the Cys-loop receptor family are essential mediators of fast neurotransmission throughout the nervous system and are implicated in many neurological disorders. Available X-ray structures of prokaryotic and eukaryotic Cys-loop receptors provide tremendous insights into the binding of agonists, the subsequent opening of the ion channel, and the mechanism of channel activation
1
,
2
,
3
,
4
,
5
,
6
,
7
,
8
. Yet the mechanism of inactivation by antagonists remains unknown. Here we present a 3.0 Å X-ray structure of the human glycine receptor-α3 homopentamer in complex with a high affinity, high-specificity antagonist, strychnine. Our structure allows us to explore in detail the molecular recognition of antagonists. Comparisons with previous structures reveal a mechanism for antagonist-induced inactivation of Cys-loop receptors, involving an expansion of the orthosteric binding site in the extracellular domain that is coupled to closure of the ion pore in the transmembrane domain.
Journal Article
Structure and Mechanism of a Na⁺-Independent Amino Acid Transporter
Amino acid, polyamine, and organocation (APC) transporters are secondary transporters that play essential roles in nutrient uptake, neurotransmitter recycling, ionic homeostasis, and regulation of cell volume. Here, we present the crystal structure of apo-ApcT, a proton-coupled broad-specificity amino acid transporter, at 2.35 angstrom resolution. The structure contains 12 transmembrane helices, with the first 10 consisting of an inverted structural repeat of 5 transmembrane helices like the leucine transporter LeuT. The ApcT structure reveals an inward-facing, apo state and an amine moiety of lysine-158 located in a position equivalent to the sodium ion site Na2 of LeuT. We propose that lysine-158 is central to proton-coupled transport and that the amine group serves the same functional role as the Na2 ion in LeuT, thus demonstrating common principles among proton- and sodium-coupled transporters.
Journal Article
Structural Basis of Androgen Receptor Binding to Selective Androgen Response Elements
Steroid receptors bind as dimers to a degenerate set of response elements containing inverted repeats of a hexameric half-site separated by 3 bp of spacer (IR3). Naturally occurring selective androgen response elements have recently been identified that resemble direct repeats of the hexameric half-site (ADR3). The 3D crystal structure of the androgen receptor (AR) DNA-binding domain bound to a selective ADR3 reveals an unexpected head-to-head arrangement of the two protomers rather than the expected head-to-tail arrangement seen in nuclear receptors bound to response elements of similar geometry. Compared with the glucocorticoid receptor, the DNA-binding domain dimer interface of the AR has additional interactions that stabilize the AR dimer and increase the affinity for nonconsensus response elements. This increased interfacial stability compared with the other steroid receptors may account for the selective binding of AR to ADR3 response elements.
Journal Article
Crystal structures of human glycine receptor α3 bound to a novel class of analgesic potentiators
The structure of GlyRα3 in complex with a selective potentiator that decreases neuropathic pain in an animal model identifies a novel allosteric regulatory mechanism.
Current therapies to treat persistent pain and neuropathic pain are limited by poor efficacy, side effects and risk of addiction. Here, we present a novel class of potent selective, central nervous system (CNS)-penetrant potentiators of glycine receptors (GlyRs), ligand-gated ion channels expressed in the CNS. AM-1488 increased the response to exogenous glycine in mouse spinal cord and significantly reversed mechanical allodynia induced by nerve injury in a mouse model of neuropathic pain. We obtained an X-ray crystal structure of human homopentameric GlyRα3 in complex with AM-3607, a potentiator of the same class with increased potency, and the agonist glycine, at 2.6-Å resolution. AM-3607 binds a novel allosteric site between subunits, which is adjacent to the orthosteric site where glycine binds. Our results provide new insights into the potentiation of cysteine-loop receptors by positive allosteric modulators and hold promise in structure-based design of GlyR modulators for the treatment of neuropathic pain.
Journal Article
Water-sensitive urban design: opportunities for the UK
Water-sensitive urban design (WSUD) is a concept that is gaining support as a means to manage urban water systems in an integrated way through the better positioning of the topic of water in urban planning and design processes. Water-sensitive urban design is emerging in the UK and this paper sets the scene and identifies the opportunities and constraints from a UK perspective. Recent developments in integrated water management, ecosystem services and multifunctional land use provide new opportunities for ‘getting more for less’. These can range from seeing all forms of water as a resource, exploiting opportunities to contribute to the green and blue infrastructure agendas, resilience to climate and other changes. This paper draws on international experience as to how water-sensitive urban design can deliver opportunities; mitigate the urban development challenges; implement and support institutional, regulatory and practical opportunities and demonstrate the benefits of taking a water-sensitive urban design approach in the UK. The key requirements for delivery are highlighted and a proposed vision for water-sensitive urban design in the UK outlined.
Journal Article
Structure of human spermine oxidase in complex with a highly selective allosteric inhibitor
Human spermine oxidase (hSMOX) plays a central role in polyamine catabolism. Due to its association with several pathological processes, including inflammation and cancer, hSMOX has garnered interest as a possible therapeutic target. Therefore, determination of the structure of hSMOX is an important step to enable drug discovery and validate hSMOX as a drug target. Using insights from hydrogen/deuterium exchange mass spectrometry (HDX-MS), we engineered a hSMOX construct to obtain the first crystal structure of hSMOX bound to the known polyamine oxidase inhibitor MDL72527 at 2.4 Å resolution. While the overall fold of hSMOX is similar to its homolog, murine
N
1-acetylpolyamine oxidase (mPAOX), the two structures contain significant differences, notably in their substrate-binding domains and active site pockets. Subsequently, we employed a sensitive biochemical assay to conduct a high-throughput screen that identified a potent and selective hSMOX inhibitor, JNJ-1289. The co-crystal structure of hSMOX with JNJ-1289 was determined at 2.1 Å resolution, revealing that JNJ-1289 binds to an allosteric site, providing JNJ-1289 with a high degree of selectivity towards hSMOX. These results provide crucial insights into understanding the substrate specificity and enzymatic mechanism of hSMOX, and for the design of highly selective inhibitors.
Rational engineering of human spermine oxidase yields crystallizable structures and the design of an allosteric inhibitor.
Journal Article
Structural basis of VDR-DNA interactions on direct repeat response elements
The vitamin D receptor (VDR) forms homo‐ or heterodimers on response elements composed of two hexameric half‐sites separated by 3 bp of spacer DNA. We describe here the crystal structures at 2.7–2.8 Å resolution of the VDR DNA‐binding region (DBD) in complex with response elements from three different promoters: osteopontin (SPP), canonical DR3 and osteocalcin (OC). These structures reveal the chemical basis for the increased affinity of VDR for the SPP response element, and for the poor stability of the VDR–OC complex, relative to the canonical DR3 response element. The homodimeric protein–protein interface is stabilized by van der Waals interactions and is predominantly non‐polar. An extensive α‐helix at the C‐terminal end of the VDR DBD resembles that found in the thyroid hormone receptor (TR), and suggests a mechanism by which VDR and TR discriminate among response elements. Selective structure‐based mutations in the asymmetric homodimeric interface result in a VDR DBD protein that is defective in homodimerization but now forms heterodimers with the 9‐
cis
retinoic acid receptor (RXR) DBD.
Journal Article
Assessing the efficiency costs of Vietnam's 'missing' small and medium sized enterprises: A panel data investigation
This article investigates whether there are efficiency costs associated with the pronounced rightward skew in the firm size distribution, or Vietnam's 'missing small and medium size enterprise (SMEs)', drawing on panel data analysis of firm growth and survival. Specifically, it examines if factor allocation biases with respect to credit, preferable treatment of state owned enterprises, barriers to entry into export markets and economies of scale are important determinants of growth rates and survival probabilities of small, medium and large-sized firms. Overall, findings on the earlier variables do not support the view that there are large efficiency costs associated with Vietnam's 'missing SMEs'. Together with other results in the literature with do not find significant equity costs associated with Vietnam's 'missing SMES', these findings raise questions about policy initiatives in support of SMEs in Vietnam, such as the National SME Support program, in particular, through improved access to credit.
Journal Article
What to Expect from Toronto’s Poverty Reduction Strategy
Les stratégies de réduction de la pauvreté de différents ordres de gouvernement ont proliféré partout au Canada au cours des récentes années. Les auteurs se demandent ce qu’il est raisonnable d’espérer de ces stratégies, en particulier de celle de la Ville de Toronto, compte tenu de l’expérience du Document de stratégie pour la réduction de la pauvreté dans l’hémisphère Sud. Ils font valoir que les limitations importantes liées au contexte de restrictions budgétaires dans lequel elles ont été mises en oeuvre, au fardeau très lourd qu’elles imposent aux secteurs sociaux et au fait qu’il s’agit souvent de simples compilations de politiques et de programmes publics existants, sans grand effort pour établir les priorités, font en sorte qu’il est peu probable que ces stratégies donnent lieu à des réductions appréciables de la pauvreté. Leur apport le plus important est d’ordre politique, et leurs répercussions sur la pauvreté sont susceptibles d’être positives quoique modestes.
Poverty reduction strategies (PRSs) have proliferated across Canada in recent years at different levels of government. In this article, we address the question of what may reasonably be expected of such strategies, in particular the city of Toronto’s PRS, drawing on the Poverty Reduction Strategy Paper experience in the Global South. We argue that key limitations related to the tight fiscal environment in which these strategies have been implemented, their very heavy weighting on the social sectors, and the fact that they are often simple compilations of existing public programs and policies with minimal prioritisation make it highly unlikely that large-scale reductions in poverty will result. Their most important contribution is political, and their impacts on poverty are likely to be positive but modest.
Journal Article