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Cell Chemical Biology

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https://www.readbyqxmd.com/read/29129717/a-chemoproteomic-approach-to-query-the-degradable-kinome-using-a-multi-kinase-degrader
#1
Hai-Tsang Huang, Dennis Dobrovolsky, Joshiawa Paulk, Guang Yang, Ellen L Weisberg, Zainab M Doctor, Dennis L Buckley, Joong-Heui Cho, Eunhwa Ko, Jaebong Jang, Kun Shi, Hwan Geun Choi, James D Griffin, Ying Li, Steven P Treon, Eric S Fischer, James E Bradner, Li Tan, Nathanael S Gray
Heterobifunctional molecules that recruit E3 ubiquitin ligases, such as cereblon, for targeted protein degradation represent an emerging pharmacological strategy. A major unanswered question is how generally applicable this strategy is to all protein targets. In this study, we designed a multi-kinase degrader by conjugating a highly promiscuous kinase inhibitor with a cereblon-binding ligand, and used quantitative proteomics to discover 28 kinases, including BTK, PTK2, PTK2B, FLT3, AURKA, AURKB, TEC, ULK1, ITK, and nine members of the CDK family, as degradable...
November 7, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29129718/lessons-in-protac-design-from-selective-degradation-with-a-promiscuous-warhead
#2
Daniel P Bondeson, Blake E Smith, George M Burslem, Alexandru D Buhimschi, John Hines, Saul Jaime-Figueroa, Jing Wang, Brian D Hamman, Alexey Ishchenko, Craig M Crews
Inhibiting protein function selectively is a major goal of modern drug discovery. Here, we report a previously understudied benefit of small molecule proteolysis-targeting chimeras (PROTACs) that recruit E3 ubiquitin ligases to target proteins for their ubiquitination and subsequent proteasome-mediated degradation. Using promiscuous CRBN- and VHL-recruiting PROTACs that bind >50 kinases, we show that only a subset of bound targets is degraded. The basis of this selectivity relies on protein-protein interactions between the E3 ubiquitin ligase and the target protein, as illustrated by engaged proteins that are not degraded as a result of unstable ternary complexes with PROTAC-recruited E3 ligases...
October 31, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29129716/the-advantages-of-targeted-protein-degradation-over-inhibition-an-rtk-case-study
#3
George M Burslem, Blake E Smith, Ashton C Lai, Saul Jaime-Figueroa, Daniel C McQuaid, Daniel P Bondeson, Momar Toure, Hanqing Dong, Yimin Qian, Jing Wang, Andrew P Crew, John Hines, Craig M Crews
Proteolysis targeting chimera (PROTAC) technology has emerged over the last two decades as a powerful tool for targeted degradation of endogenous proteins. Herein we describe the development of PROTACs for receptor tyrosine kinases, a protein family yet to be targeted for induced protein degradation. The use of VHL-recruiting PROTACs against this protein family reveals several advantages of degradation over inhibition alone: direct comparisons of fully functional, target-degrading PROTACs with target-inhibiting variants that contain an inactivated E3 ligase-recruiting ligand show that degradation leads to more potent inhibition of cell proliferation and a more durable and sustained downstream signaling response, and thus addresses the kinome rewiring challenge seen with many receptor tyrosine kinase inhibitors...
October 25, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29104065/design-and-profiling-of-a-subcellular-targeted-optogenetic-camp-dependent-protein-kinase
#4
Colin P O'Banion, Melanie A Priestman, Robert M Hughes, Laura E Herring, Stephen J Capuzzi, David S Lawrence
Although the cAMP-dependent protein kinase (PKA) is ubiquitously expressed, it is sequestered at specific subcellular locations throughout the cell, thereby resulting in compartmentalized cellular signaling that triggers site-specific behavioral phenotypes. We developed a three-step engineering strategy to construct an optogenetic PKA (optoPKA) and demonstrated that, upon illumination, optoPKA migrates to specified intracellular sites. Furthermore, we designed intracellular spatially segregated reporters of PKA activity and confirmed that optoPKA phosphorylates these reporters in a light-dependent fashion...
October 25, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29104064/a-chemical-proteomics-approach-to-reveal-direct-protein-protein-interactions-in-living-cells
#5
Ralph E Kleiner, Lisa E Hang, Kelly R Molloy, Brian T Chait, Tarun M Kapoor
Protein-protein interactions mediate essential cellular processes, however the detection of native interactions is challenging since they are often low affinity and context dependent. Here, we develop a chemical proteomics approach in vivo CLASPI [iCLASPI] (in vivo crosslinking-assisted and stable isotope labeling by amino acids in cell culture [SILAC]-based protein identification) relying upon photo-crosslinking, amber suppression, and SILAC-based quantitative proteomics to profile context-dependent protein-protein interactions in living cells...
October 25, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29104063/dynamics-of-proofreading-by-the-e-%C3%A2-coli-pol-iii-replicase
#6
Jonghyun Park, Slobodan Jergic, Yongmoon Jeon, Won-Ki Cho, Ryanggeun Lee, Nicholas E Dixon, Jong-Bong Lee
The αɛθ core of Escherichia coli DNA polymerase III (Pol III) associates with the β2 sliding clamp to processively synthesize DNA and remove misincorporated nucleotides. The α subunit is the polymerase while ɛ is the 3' to 5' proofreading exonuclease. In contrast to the polymerase activity of Pol III, dynamic features of proofreading are poorly understood. We used single-molecule assays to determine the excision rate and processivity of the β2-associated Pol III core, and observed that both properties are enhanced by mutational strengthening of the interaction between ɛ and β2...
October 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29107701/b-%C3%A2-subtilis-lytr-cpsa-psr-enzymes-transfer-wall-teichoic-acids-from-authentic-lipid-linked-substrates-to-mature-peptidoglycan-in%C3%A2-vitro
#7
Robert T Gale, Franco K K Li, Tianjun Sun, Natalie C J Strynadka, Eric D Brown
Gram-positive bacteria endow their peptidoglycan with glycopolymers that are crucial for viability and pathogenesis. However, the cellular machinery that executes this function is not well understood. While decades of genetic and phenotypic work have highlighted the LytR-CpsA-Psr (LCP) family of enzymes as cell-wall glycopolymer transferases, their in vitro characterization has been elusive, largely due to a paucity of tools for functional assays. In this report, we synthesized authentic undecaprenyl diphosphate-linked wall teichoic acid (WTA) intermediates and built an assay system capable of monitoring LCP-mediated glycopolymer transfer...
October 12, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29107700/general-and-modular-strategy-for-designing-potent-selective-and-pharmacologically-compliant-inhibitors-of-rhomboid-proteases
#8
Anežka Tichá, Stancho Stanchev, Kutti R Vinothkumar, David C Mikles, Petr Pachl, Jakub Began, Jan Škerle, Kateřina Švehlová, Minh T N Nguyen, Steven H L Verhelst, Darren C Johnson, Daniel A Bachovchin, Martin Lepšík, Pavel Majer, Kvido Strisovsky
Rhomboid-family intramembrane proteases regulate important biological processes and have been associated with malaria, cancer, and Parkinson's disease. However, due to the lack of potent, selective, and pharmacologically compliant inhibitors, the wide therapeutic potential of rhomboids is currently untapped. Here, we bridge this gap by discovering that peptidyl α-ketoamides substituted at the ketoamide nitrogen by hydrophobic groups are potent rhomboid inhibitors active in the nanomolar range, surpassing the currently used rhomboid inhibitors by up to three orders of magnitude...
October 12, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29107699/synthetic-three-component-hiv-1-v3-glycopeptide-immunogens-induce-glycan-dependent-antibody-responses
#9
Hui Cai, Jared Orwenyo, John P Giddens, Qiang Yang, Roushu Zhang, Celia C LaBranche, David C Montefiori, Lai-Xi Wang
Eliciting broadly neutralizing antibody (bNAb) responses against HIV-1 is a major goal for a prophylactic HIV-1 vaccine. One approach is to design immunogens based on known broadly neutralizing epitopes. Here we report the design and synthesis of an HIV-1 glycopeptide immunogen derived from the V3 domain. We performed glycopeptide epitope mapping to determine the minimal glycopeptide sequence as the epitope of V3-glycan-specific bNAbs PGT128 and 10-1074. We further constructed a self-adjuvant three-component immunogen that consists of a 33-mer V3 glycopeptide epitope, a universal T helper epitope P30, and a lipopeptide (Pam3CSK4) that serves as a ligand of Toll-like receptor 2...
October 4, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29056420/usp7-specific-inhibitors-target-and-modify-the-enzyme-s-active-site-via-distinct-chemical-mechanisms
#10
Alexandra Pozhidaeva, Gabrielle Valles, Feng Wang, Jian Wu, David E Sterner, Phuong Nguyen, Joseph Weinstock, K G Suresh Kumar, Jean Kanyo, Dennis Wright, Irina Bezsonova
USP7 is a deubiquitinating enzyme that plays a pivotal role in multiple oncogenic pathways and therefore is a desirable target for new anti-cancer therapies. However, the lack of structural information about the USP7-inhibitor interactions has been a critical gap in the development of potent inhibitors. USP7 is unique among USPs in that its active site is catalytically incompetent, and is postulated to rearrange into a productive conformation only upon binding to ubiquitin. Surprisingly, we found that ubiquitin alone does not induce an active conformation in solution...
October 4, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29056421/structure-guided-development-of-a-potent-and-selective-non-covalent-active-site-inhibitor-of-usp7
#11
Ilaria Lamberto, Xiaoxi Liu, Hyuk-Soo Seo, Nathan J Schauer, Roxana E Iacob, Wanyi Hu, Deepika Das, Tatiana Mikhailova, Ellen L Weisberg, John R Engen, Kenneth C Anderson, Dharminder Chauhan, Sirano Dhe-Paganon, Sara J Buhrlage
Deubiquitinating enzymes (DUBs) have garnered significant attention as drug targets in the last 5-10 years. The excitement stems in large part from the powerful ability of DUB inhibitors to promote degradation of oncogenic proteins, especially proteins that are challenging to directly target but which are stabilized by DUB family members. Highly optimized and well-characterized DUB inhibitors have thus become highly sought after tools. Most reported DUB inhibitors, however, are polypharmacological agents possessing weak (micromolar) potency toward their primary target, limiting their utility in target validation and mechanism studies...
September 28, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29033316/synergy-and-target-promiscuity-drive-structural-divergence-in-bacterial-alkylquinolone-biosynthesis
#12
Yihan Wu, Mohammad R Seyedsayamdost
Microbial natural products are genetically encoded by dedicated biosynthetic gene clusters (BGCs). A given BGC usually produces a family of related compounds that share a core but contain variable substituents. Though common, the reasons underlying this divergent biosynthesis are in general unknown. Herein, we have addressed this issue using the hydroxyalkylquinoline (HAQ) family of natural products synthesized by Burkholderia thailandensis. Investigations into the detailed functions of two analogs show that they act synergistically in inhibiting bacterial growth...
September 28, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29056419/fungal-cordycepin-biosynthesis-is-coupled-with-the-production-of-the-safeguard-molecule-pentostatin
#13
Yongliang Xia, Feifei Luo, Yanfang Shang, Peilin Chen, Yuzhen Lu, Chengshu Wang
Cordycepin (COR) and pentostatin (PTN) are adenosine analogs with related bioactivity profiles as both mimic adenosine and can inhibit some of the processes that are adenosine dependent. Both COR and PTN are also natural products and were originally isolated from the fungus Cordyceps militaris and the bacterium Streptomyces antibioticus, respectively. Here, we report that not only is PTN produced by C. militaris but that biosynthesis of COR is coupled with PTN production by a single gene cluster. We also demonstrate that this coupling is an important point of metabolic regulation where PTN safeguards COR from deamination by inhibiting adenosine deaminase (ADA) activity...
September 27, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29033318/an-alkynyl-fucose-halts-hepatoma-cell-migration-and-invasion-by-inhibiting-gdp-fucose-synthesizing-enzyme-fx-tsta3
#14
Yasuhiko Kizuka, Miyako Nakano, Yoshiki Yamaguchi, Kazuki Nakajima, Ritsuko Oka, Keiko Sato, Chien-Tai Ren, Tsui-Ling Hsu, Chi-Huey Wong, Naoyuki Taniguchi
Fucosylation is a glycan modification critically involved in cancer and inflammation. Although potent fucosylation inhibitors are useful for basic and clinical research, only a few inhibitors have been developed. Here, we focus on a fucose analog with an alkyne group, 6-alkynyl-fucose (6-Alk-Fuc), which is used widely as a detection probe for fucosylated glycans, but is also suggested for use as a fucosylation inhibitor. Our glycan analysis using lectin and mass spectrometry demonstrated that 6-Alk-Fuc is a potent and general inhibitor of cellular fucosylation, with much higher potency than the existing inhibitor, 2-fluoro-fucose (2-F-Fuc)...
September 19, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29033317/ras-binder-induces-a-modified-switch-ii-pocket-in-gtp-and-gdp-states
#15
Daniel R Gentile, Manoj K Rathinaswamy, Meredith L Jenkins, Steven M Moss, Braden D Siempelkamp, Adam R Renslo, John E Burke, Kevan M Shokat
Covalent inhibitors of K-Ras(G12C) have been reported that exclusively recognize the GDP state. Here, we utilize disulfide tethering of a non-natural cysteine (K-Ras(M72C)) to identify a new switch-II pocket (S-IIP) binding ligand (2C07) that engages the active GTP state. Co-crystal structures of 2C07 bound to H-Ras(M72C) reveal binding in a cryptic groove we term S-IIG. In the GppNHp state, 2C07 binding to a modified S-IIP pushes switch I away from the nucleotide, breaking the network of polar contacts essential for adopting the canonical GTP state...
September 19, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29033315/very-long-chain-fatty-acids-are-functionally-involved-in-necroptosis
#16
Laura R Parisi, Nasi Li, G Ekin Atilla-Gokcumen
Necroptosis is a form of regulated cell death that is linked to various human diseases. Distinct membrane-related, thus lipid-dependent, alterations take place during necroptosis. However, little is known about the roles of specific lipids in this process. We used an untargeted LC-MS-based approach to reveal that distinct lipid species are regulated at the molecular level during necroptosis. We found that ceramides and very long chain fatty acids accumulate during this process. Intrigued by the specificity of very long chain fatty acid accumulation, we focused on characterizing their involvement during necroptosis...
September 18, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29149590/just-a-spoonful-of-sugar-htlv-1-style
#17
Naomi Taylor
Host cell metabolism regulates viral infection. In this issue of Cell Chemical Biology, Kulkarni et al. (2017) reveal the importance of oxygen concentrations and glycolysis in the reactivation of human T cell leukemia virus (HTLV-1). Identifying the host metabolic networks that regulate infection will foster our understanding of HTLV-1-associated pathologies.
November 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29149589/bond-with-me-if-you-can-natural-product-covalent-ligand-and-reactivity-based-probe-compete-for-cysteine-in-pp2a-complex
#18
Douglas S Johnson, Jaimeen D Majmudar
In this issue of Cell Chemical Biology, Grossman et al. (2017) disclose a chemoproteomics-enabled strategy to identify the cysteine-reactive target(s) of the anti-cancer natural product withaferin A and then screen a cysteine-reactive fragment library to discover a covalent ligand for the same target.
November 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29149588/nih-support-for-fda-approved-medicines
#19
LETTER
Rebekah H Griesenauer, Ryan Moore, Michael S Kinch
No abstract text is available yet for this article.
November 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28988949/structure-of-the-guanidine-iii-riboswitch
#20
Lin Huang, Jia Wang, Timothy J Wilson, David M J Lilley
Riboswitches are structural elements found in mRNA molecules that couple small-molecule binding to regulation of gene expression, usually by controlling transcription or translation. We have determined high-resolution crystal structures of the ykkC guanidine III riboswitch from Thermobifida fusca. The riboswitch forms a classic H-type pseudoknot that includes a triple helix that is continuous with a central core of conserved nucleotides. These form a left-handed helical ramp of inter-nucleotide interactions, generating the guanidinium cation binding site...
November 16, 2017: Cell Chemical Biology
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