Abstract：
:Small-molecule inhibitors of kinesin-5 (refs. 1-3), a protein essential for eukaryotic cell division, represent alternatives to antimitotic agents that target tubulin. While tubulin is needed for multiple intracellular processes, the known functions of kinesin-5 are limited to dividing cells, making it likely that kinesin-5 inhibitors would have fewer side effects than do tubulin-targeting drugs. Kinesin-5 inhibitors, such as monastrol, act through poorly understood allosteric mechanisms, not competing with ATP binding. Moreover, the microscopic mechanism of full-length kinesin-5 motility is not known. Here we characterize the motile properties and allosteric inhibition of Eg5, a vertebrate kinesin-5, using a GFP fusion protein in single-molecule fluorescence assays. We find that Eg5 is a processive kinesin whose motility includes, in addition to ATP-dependent directional motion, a diffusive component not requiring ATP hydrolysis. Monastrol suppresses the directional processive motility of microtubule-bound Eg5. These data on Eg5's allosteric inhibition will impact these inhibitors' use as probes and development as chemotherapeutic agents.
journal_name
Nat Chem Bioljournal_title
Nature chemical biologyauthors
Kwok BH,Kapitein LC,Kim JH,Peterman EJ,Schmidt CF,Kapoor TMdoi
10.1038/nchembio812subject
Has Abstractpub_date
2006-09-01 00:00:00pages
480-5issue
9eissn
1552-4450issn
1552-4469pii
nchembio812journal_volume
2pub_type
杂志文章abstract：:Lipid rafts in plasma membranes have emerged as possible platforms for the entry of HIV and other viruses into cells. However, little is known about how lipid phase heterogeneity contributes to viral entry because of the fine-grained and still poorly understood complexity of biological membranes. We used model systems...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1800
更新日期：2015-06-01 00:00:00
abstract：:Protein kinase signaling along the kinetochore-centromere axis is crucial to assure mitotic fidelity, yet the details of its spatial coordination are obscure. Here, we examined how pools of human Polo-like kinase 1 (Plk1) within this axis control signaling events to elicit mitotic functions. To do this, we restricted ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2060
更新日期：2016-06-01 00:00:00
abstract：:Transient receptor potential (TRP) proteins form plasma-membrane cation channels that act as sensors for diverse cellular stimuli. Here, we report a novel activation mechanism mediated by cysteine S-nitrosylation in TRP channels. Recombinant TRPC1, TRPC4, TRPC5, TRPV1, TRPV3 and TRPV4 of the TRPC and TRPV families, wh...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio821
更新日期：2006-11-01 00:00:00
abstract：:Lysostaphin is a bacteriolytic enzyme targeting peptidoglycan, the essential component of the bacterial cell envelope. It displays a very potent and specific activity toward staphylococci, including methicillin-resistant Staphylococcus aureus. Lysostaphin causes rapid cell lysis and disrupts biofilms, and is therefore...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-019-0393-4
更新日期：2020-01-01 00:00:00
abstract：:Intrinsically disordered regions (IDRs) of proteins often regulate function upon post-translational modification (PTM) through interactions with folded domains. An IDR linking two α-helices (α1-α2) of the antiapoptotic protein Bcl-xL experiences several PTMs that reduce antiapoptotic activity. Here, we report that PTM...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-018-0011-x
更新日期：2018-05-01 00:00:00
abstract：:N(1)-Methyladenosine (m(1)A) is a prevalent post-transcriptional RNA modification, yet little is known about its abundance, topology and dynamics in mRNA. Here, we show that m(1)A is prevalent in Homo sapiens mRNA, which shows an m(1)A/A ratio of ∼0.02%. We develop the m(1)A-ID-seq technique, based on m(1)A immunoprec...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2040
更新日期：2016-05-01 00:00:00
abstract：:The resistance of Caenorhabditis elegans to pharmacological perturbation limits its use as a screening tool for novel small bioactive molecules. One strategy to improve the hit rate of small-molecule screens is to preselect molecules that have an increased likelihood of reaching their target in the worm. To learn whic...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.380
更新日期：2010-07-01 00:00:00
abstract：:We describe a new technology for recruiting specific proteins to RNA through selective recognition of heteroduplexes formed with chemically modified antisense oligonucleotides (ASOs). Typically, ASOs function by hybridizing to their RNA targets and blocking the binding of single-stranded RNA-binding proteins. Unexpect...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.939
更新日期：2012-04-15 00:00:00
abstract：:Cysteine dioxygenase (CDO) plays an essential role in sulfur metabolism by regulating homeostatic levels of cysteine. Human CDO contains a post-translationally generated Cys93-Tyr157 cross-linked cofactor. Here, we investigated this Cys-Tyr cross-linking by incorporating unnatural tyrosines in place of Tyr157 via a ge...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-018-0085-5
更新日期：2018-09-01 00:00:00
abstract：:Cyclin-dependent kinase 9 (CDK9), an important regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. We characterized NVP-2, a selective ATP-competitive CDK9 inhibitor, and THAL-SNS-032, a selective CDK9 degrader consisting ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2538
更新日期：2018-02-01 00:00:00
abstract：:The lasso peptide microcin J25 is known to hijack the siderophore receptor FhuA for initiating internalization. Here, we provide what is to our knowledge the first structural evidence on the recognition mechanism, and our biochemical data show that another closely related lasso peptide cannot interact with FhuA. Our w...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1499
更新日期：2014-05-01 00:00:00
abstract：:In response to decreasing Ca2+ levels in the endoplasmic reticulum, STIM proteins couple with Orai channels in the plasma membrane, leading to Ca2+ influx into the cell. In addition to Ca2+-related endoplasmic reticulum stress, STIM proteins are emerging as general stress sensors that react to multiple stress signals ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.619
更新日期：2011-07-18 00:00:00
abstract：: ...
journal_title：Nature chemical biology
pub_type： 评论,杂志文章
doi：10.1038/s41589-018-0073-9
更新日期：2018-06-01 00:00:00
abstract：:The inability of cells to properly fold, modify and assemble secretory and transmembrane proteins leads to accumulation of misfolded proteins in the endoplasmic reticulum (ER). Under these conditions of 'ER stress', cell survival depends on homeostatic benefits from an intracellular signaling pathway called the unfold...
journal_title：Nature chemical biology
pub_type： 杂志文章,评审
doi：10.1038/nchembio.1664
更新日期：2014-11-01 00:00:00
abstract：:Mutation and aberrant expression of apoptotic proteins are hallmarks of cancer. These changes prevent proapoptotic signals from being transmitted to executioner caspases, thereby averting apoptotic death and allowing cellular proliferation. Caspase-3 is the key executioner caspase, and it exists as an inactive zymogen...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio814
更新日期：2006-10-01 00:00:00
abstract：:Bacteria are thought to cope with fluctuating environmental solute concentrations primarily by adjusting the osmolality of their cytoplasm. To obtain insights into the underlying metabolic adaptations, we analyzed the global metabolic response of Escherichia coli to sustained hyperosmotic stress using nontargeted mass...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1437
更新日期：2014-04-01 00:00:00
abstract：:Methods for imaging and tracking single molecules conjugated with fluorescent probes, called single-molecule tracking (SMT), are now providing researchers with the unprecedented ability to directly observe molecular behaviors and interactions in living cells. Current SMT methods are achieving almost the ultimate spati...
journal_title：Nature chemical biology
pub_type： 杂志文章,评审
doi：10.1038/nchembio.1558
更新日期：2014-07-01 00:00:00
abstract：:N6-Methyladenosine (m6A) RNA modification is present in messenger RNAs (mRNA), ribosomal RNAs (rRNA), and spliceosomal RNAs (snRNA) in humans. Although mRNA m6A modifications have been extensively studied and shown to play critical roles in many cellular processes, the identity of m6A methyltransferases for rRNAs and ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-018-0184-3
更新日期：2019-01-01 00:00:00
abstract：:Excessive aggregation of proteins has a major impact on cell fate and is a hallmark of amyloid diseases in humans. To resolve insoluble deposits and to maintain protein homeostasis, all cells use dedicated protein disaggregation, protein folding and protein degradation factors. Despite intense recent research, the und...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1931
更新日期：2015-11-01 00:00:00
abstract：:Phosphorylation and glycosylation of the tau protein, which is implicated in neurodegenerative diseases, are intimately linked. In vivo pharmacological inhibition of tau deglycosylation may be a new way to suppress abnormal tau phosphorylation, known to be involved in the formation of neurofibrillary tangles in the br...
journal_title：Nature chemical biology
pub_type： 评论,杂志文章,评审
doi：10.1038/nchembio0808-448
更新日期：2008-08-01 00:00:00
abstract：:Lysine riboswitches are bacterial RNA structures that sense the concentration of lysine and regulate the expression of lysine biosynthesis and transport genes. Members of this riboswitch class are found in the 5' untranslated region of messenger RNAs, where they form highly selective receptors for lysine. Lysine bindi...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio842
更新日期：2007-01-01 00:00:00
abstract：:Proper gene expression is essential for the survival of every cell. Once thought to be a passive transporter of genetic information, RNA has recently emerged as a key player in nearly every pathway in the cell. A full description of its structure is critical to understanding RNA function. Decades of research have focu...
journal_title：Nature chemical biology
pub_type： 杂志文章,评审
doi：10.1038/nchembio.1958
更新日期：2015-12-01 00:00:00
abstract：:Combination antiretroviral therapy has transformed HIV-1 infection, once a fatal illness, into a manageable chronic condition. Drug resistance, severe side effects and treatment noncompliance bring challenges to combination antiretroviral therapy implementation in clinical settings and indicate the need for additional...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-020-0496-y
更新日期：2020-05-01 00:00:00
abstract：:It is postulated that in addition to cell density, other factors such as the dimensions and diffusional characteristics of the environment could influence quorum sensing (QS) and induction of genetic reprogramming. Modeling studies predict that QS may operate at the level of a single cell, but, owing to experimental c...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.264
更新日期：2010-01-01 00:00:00
abstract：:Synthetic mRNA is an attractive vehicle for gene therapies because of its transient nature and improved safety profile over DNA. However, unlike DNA, broadly applicable methods to control expression from mRNA are lacking. Here we describe a platform for small-molecule-based regulation of expression from modified RNA (...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-018-0146-9
更新日期：2018-11-01 00:00:00
abstract：:The chemical scaffolds from which screening libraries are built have strong influence on the libraries' utility for screening campaigns. Here we present analysis of the scaffold composition of several types of commercially available screening collections and compare those compositions to those of drugs and drug candid...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio0807-442
更新日期：2007-08-01 00:00:00
abstract：:Here we identify the amino acid transporter AnsP1 as the unique aspartate importer in the human pathogen Mycobacterium tuberculosis. Metabolomic analysis of a mutant with an inactive AnsP1 revealed that the transporter is essential for M. tuberculosis to assimilate nitrogen from aspartate. Virulence of the AnsP1 mutan...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1355
更新日期：2013-11-01 00:00:00
abstract：:The rise of antibiotic resistance demands the acceleration of molecular diversification strategies to inspire new chemical entities for antibiotic medicines. We report here on the large-scale engineering of ribosomally synthesized and post-translationally modified antimicrobial peptides carrying the ring-forming amino...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-019-0250-5
更新日期：2019-05-01 00:00:00
abstract：:The phytohormone auxin indole-3-acetic acid (IAA) regulates nearly all aspects of plant growth and development. Despite substantial progress in our understanding of auxin biology, delineating specific auxin response remains a major challenge. Auxin regulates transcriptional response via its receptors, TIR1 and AFB F-b...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2555
更新日期：2018-03-01 00:00:00
abstract：:We describe Scaffold Hunter, a highly interactive computer-based tool for navigation in chemical space that fosters intuitive recognition of complex structural relationships associated with bioactivity. The program reads compound structures and bioactivity data, generates compound scaffolds, correlates them in a hiera...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.187
更新日期：2009-08-01 00:00:00
