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Wdr 161 VideoMausSpots Folge 10 - Die Sendung mit der Maus - WDR
Probably due to their versatility as protein interaction scaffolds, WDRs are the fourth most abundant domain in the human proteome An algorithm that is comparatively sensitive to WD repeats was recently developed to annotate WDR proteins 20 , Additionally, in yeast, where the interactome is best characterized, WDR domains are engaged in more protein-protein interactions than any other domain 15 , emphasizing the ubiquitous role of these domains in connecting the global protein interaction network.
As a consequence of their prevalence in the human proteome, WDR domains are involved in a wide spectrum of cellular networks, many of which are perturbed in human diseases.
Cellular pathways from the Reactome database 23 were ranked based on the number of WDR proteins involved Fig. At the top of the list, at least 49 WDR proteins are known to participate in the regulation of gene expression.
Among these, 15 are components of chromatin complexes, including EED and WDR5, for which potent inhibitors have been reported 24 — WDRs are also found in pathways that are targeted by existing drugs, such as DNA repair or the immune system, in emerging areas of drug discovery, such as chromatin mediated signaling or splicing, and in cellular networks that have so far proven largely undruggable, such as the extensive ubiquitin-proteasome system UPS that exerts post-translational control over most of the proteome.
In some cases, disease association is direct and causative. Loss-of-function mutations in FBXW7, including a mutation hot-spot at R, the side-chain that recognizes the phosphothreonine, lead to accumulation of Cyclin-E, and are recurrent driver events in endometrial, colorectal and other cancers 27 Fig.
In another example, mapping missense variations from clinical and population genetics onto the 3D structure of the WDR protein TBL1XR1 clearly separates pathogenic mutations that are responsible for severe neurological disorders in children from benign polymorphisms The number of WDR proteins associated with Reactome pathways and corresponding enrichment compared with the whole proteome are indicated.
Specific disease-associated examples are shown in colored boxes. WDR proteins are not only associated with disease gene networks, but many are target candidates for therapy in cancer, metabolic disorders, neurological diseases and regenerative medicine Table 1.
Epigenetic mechanisms are now recognized as being central to the etiology of many cancers 29 , 30 and proteins involved in chromatin mediated signaling are a promising target class for cancer therapy 31 , At least 15 WDR proteins are components of chromatin complexes Fig.
For example, pharmacological inhibition of WDR5 has recently emerged as a promising strategy in oncology.
MLL1 in turn methylates lysine 4 of histone 3 H3K4 , an epigenetic signal associated with active gene transcription, resulting in a pdependent inhibition of myeloid differentiation.
Another study with the WDR5 inhibitor exploited the observation that prevalent cancer-promoting gain-of-function mutations of TP53 lead to up-regulation of MLL1 and MLL2, a global increase of histone methylation, and proliferation of cancer cells.
A related study was based on the observation that leukemogenesis induced by the MLL-AF9 fusion protein requires co-expression of the wild-type MLL1 allele MM, a macrocyclic inhibitor of WDR5, inhibited wild-type MLL1 and induced myeloid differentiation of mixed lineage leukemia cells, with no apparent toxicity on normal bone marrow cells Research groups from Novartis, and Abbvie in collaboration with the Structural Genomics Consortium have independently shown that drug-like inhibitors targeting the WDR domain of EED antagonize binding of an activating peptide that is necessary for the proper propagation of the methyl mark deposited by PRC2 Fig.
The compounds inhibit PRC2 in cells with low nanomolar IC 50s , and remain active against PRC2-mutated cell lines that are resistant to catalytic inhibitors currently in clinical trial in oncology 25 , Though encouraging, how these results will translate in pre-clinical and clinical development is still an open question.
The structural role of RBBP4 in different complexes and its function in transcriptional reprogramming of cancer cells is not clear, but probably varies with cancer types and grades.
WDR77, another WDR protein involved in epigenetic control of gene expression, directly binds to the methyltransferase PRMT5 to promote symmetrical dimethylation of arginine side-chains on histone and non-histone substrates.
The PRMT5-WDR77 complex was also shown to remodel gene expression to promote epithelial-to-mesenchymal transition and cancer cell invasion Many WDR proteins are implicated in cancer-associated cellular pathways beyond epigenetic mechanisms.
Thirteen or more WDR proteins play a role in the ubiquitin proteasome system. One of these, Cell division cycle protein 20 homolog CDC20 , is a co-activator of the anaphase promoting complex APC E3 ubiquitin ligase that recruits substrates for subsequent ubiquitination and drives mitosis CDC20 is one of two genes that are systematically upregulated in glioblastoma versus low-grade gliomas, drives the invasiveness and self-renewal of glioblastoma stem-like cells, and CDC20 knockdown induces cell cycle arrest and apoptosis in glioblastoma tumor initiating cells 49 — These results suggest that small molecules disrupting the interaction between CDC20 and APC, or antagonizing CDCmediated recruitment of APC substrates could have therapeutic value against glioblastoma, and potentially other cancer types.
Genetic aberrations recurrently found in cancer often drive tumor initiation or tumor growth. In both cases, chemical inhibitors targeting the kinase domain of the oncogenic fusion protein have anti-proliferative effect 52 , 54 , and pharmacological targeting of the WDR domain may be an alternative strategy against tumors with SEC31A translocations.
WDR proteins are promising candidate targets in the emerging field of regenerative medicine. CHAF1B knockdown increased chromatin accessibility at enhancer domains associated with activation of pluripotency genes, confirming an epigenetic function of CHAF1B in maintaining somatic cell identity.
Interestingly, WDR5 has also recently been associated with pluripotency. The WDR protein platelet activating factor acetylhydrolase 1b regulatory subunit 1 PAFAH1B1, also know as LIS1 is required for actin polymerization in cerebellar and hippocampal neurons, and functions with dynein to mediate coupling of the nucleus to the centrosome in neuronal migration Deletion and point mutations of PAFAH1B1 cause neuronal migration defects, and can lead to neurological disorders and brain malformation 66 , Conversely, overexpression of PAFAH1B1 resulting from genomic amplification is associated with cerebellar atrophy in human, and transgenic mice overexpressing PAFAH1B1 have impaired neural migration and smaller brain The CT synonymous polymorphism results in a splice variant with increased G protein activation and is associated with hypertension, diabetes and obesity 77 , Duplication of a genomic region encompassing GNB3 is recurrently observed in children with a syndrome associated with obesity, intellectual disability, and seizures, and transgenic mice carrying an extra copy of GNB3 have an increased body mass index These results connect GNB3 gene dosage to obesity.
Receptor for activated C kinase 1 RACK1 is a ubiquitous WDR protein that acts as a binding scaffold with a diverse array of interactors, including protein kinases, membrane receptors and 40S ribosomal subunits, and is associated with multiple, cell type—specific functions 80 , RACK1 also facilitates translation by internal ribosome entry site IRES -containing viruses and is an essential host factor for HCV infection, such that it may represent a broad antiviral target Considering the ubiquitous nature and multiple functions of RACK1, the effects of its inhibition may depend on cell-type context, although silencing of RACK1 does not seem to overly affect cell viability and proliferation Compounds that target the WDR domain of DCAF1 may thus antagonize the illicit degradation of host defense factors by different viruses.
Considering that WDR domains are ubiquitous and often disease-associated, it comes as a surprise that only four WDR proteins have been targeted pharmacologically so far: human WDR5, EED, CDC20 and yeast Cdc4 24 — 26 , 89 , 90 These four published cases can be further grouped into two categories, depending on the specific location of the inhibitors.
The WDR5 and EED inhibitors occupy the central pocket and bind with nanomolar potency 24 — 26 , while the other inhibitors occupy side cavities and bind in the micromolar range 89 , 90 Figure 4a.
OICR, a potent and selective chemical probe targeting WDR5, was derived from a hit from a medium-throughput screen of a diverse library of 16, compounds using a fluorescence polarization assay to measure the displacement of MLL1 peptide, followed by multiple rounds of structure-guided optimization 24 , 91 — A, a potent and novel protein-protein interaction inhibitor that binds EED to inhibit the PRC2 complex, was initially identified via a high-throughput, small molecule screen utilizing a thermal shift assay TSA with EED protein, and subsequently optimized by incorporating a strategic sp 3 -rich ring constraint and appending polar functionalities to increase potency while decreasing cLogP 25 , EED26, another EED-targeting chemical probe, was discovered via a high-throughput campaign to find compounds inhibiting the catalytic activity of the reconstituted PRC2 complex Elucidating the mechanism of action of the screening hit enabled structure-guided fragmentation, regrowth and optimization into a potent, selective EED inhibitor 95 , A and EED display target-based cellular activity and significant in vivo efficacy in mouse tumor models and are valuable chemical tools to further interrogate the role of the PRC2 complex in tumor initiation and maintenance 25 , Small molecule ligands that bind WDRs on the side of the donut naturally tend to insert between the WD40 blades and may occlude substrate interactions, as in the case of the Cdc20 inhibitor apcin, which competitively blocks interaction of the destruction box D-box motif in APC substrates The conformational flexibility of WDRs also lends itself to allosteric control of protein interactions, as illustrated in the case of Cdc4, the yeast ortholog of human FBWX7.
A small molecule called SCF-I2 binds to a cryptic allosteric pocket on the side of the WD40 domain of Cdc4 and thereby triggers an elaborate series of main chain rearrangements that result in partial occlusion of the main binding pocket that recognizes Cdc4 phospho-degron CPD motifs in substrates Interestingly, NMR evidence suggests that the allosteric pocket also interacts weakly with CPD motifs, suggesting a mechanism whereby multi-CPD substrates may engender the dynamic exchange of sites in the main binding pocket in a single WD40 Whether other WDR proteins are susceptible to allosteric inhibition remains to be seen.
This structural diversity even extends to cases when pockets share similar ligands. This suggests that achieving selectivity within this target class may not be as much of a challenge as for other protein classes that share binding pockets with similar chemical features, such as kinases or bromodomains.
Conformational rearrangement of a limited number of side-chains can have dramatic impact on the size and geometry of the WDR central pocket.
In particular, F obstructs the cavity in the apo state, is partially open in the inhibitor-bound state, and is forced by the arginine of the MLL peptide into a fully open state where the bottom of the cavity disappears and the pocket is replaced with a tunnel that connects both sides of the WDR domain Fig 5a—c 24 , While the pocket is shallow in the apo and histone-bound states, conformational rearrangement of Y and adjacent residues engaged either directly or indirectly in aromatic cage formation produces a larger, deeper cavity that can accommodate small-molecule inhibitors Fig 5d—f 25 , 26 , 94 — Conformational rearrangement of a few side-chains can induce dramatic changes in the volume and enclosure of the central pockets of WDR5 a—c or EED d—f.
Conformations of mobile side-chains and associated pocket volumes are shown for apo, peptide-bound and inhibitor-bound structures.
Considering their ubiquitous nature, disease association, structural diversity and encouraging druggability, it is surprising that WDRs have so far been largely neglected by the drug discovery community.
One explanation may be that WD40 domains are typically scaffolding rather than catalytic subunits of protein complexes.
To inhibit a methyltranferase, a deubiquitinase or a histone acetyltransferase, the natural inclination is to target the catalytic domain, particularly if a well-defined druggable pocket is evident.
However, targeting the catalytic site is not always readily achievable, and for many enzyme classes this is still very challenging. For instance, despite its potential as an oncology target, no catalytic inhibitor of the methyltransferases MLL1 has been reported to date.
Similarly, some of the intense but so far unsuccessful drug discovery efforts that have focused on ubiquitin ligases and deubiquitinases for the past decade might be more effective if redirected towards the numerous WDR domains implicated in the UPS Fig.
Targeting WDRs that bind to druggable enzymes can also have merit. The epigenetic regulator PRC2 is an instructive example to consider.
Prolonged treatment of cancer cells with catalytic domain inhibitors of the PRC2 complex elicits a resistance mechanism triggered by mutations at the inhibitor-binding site.
However, allosteric inhibitors targeting the WDR subunit, EED 25 , 26 , retain on-target inhibition in cells resistant to catalytic inhibitors.
Moreover, unlike catalytic inhibitors, prolonged treatment with an EED inhibitor failed to select for resistance mutations Thus, targeting the WDR domain interaction hub of PRC2 offers several complementary approaches compared to targeting the catalytic domain.
The variability in shape and electrostatics of the WDR central pocket suggests that this protein family harbours a continuum of structures with varying degrees of chemical tractability.
Where WDR domains behave as docking platforms for electrostatically-charged peptides, it will be challenging to find inhibitors sufficiently polar to compete with substrates, while simultaneously sufficiently hydrophobic to cross cell membranes.
It is also unclear whether the weak-binding compounds targeting side-pockets of WDR domains reflect fundamentally poor druggability of these sites, or simply the paucity of drug-discovery efforts focused on these sites to date.
Considering the size of the WDR family, and recent progresses in targeting protein-protein interactions, we expect that additional WDR proteins will prove druggable in the future.
An unknown variable in targeting WDR domains is the potential effects of perturbing multiple protein complexes. For instance, RBBP7 is part of the type B histone acetyltransferase complex required for chromatin assembly following DNA replication, but is also a component of the NURD histone deacetylase and nucleosome remodeling complex and the PRC2 methyltransferase complex, all three of which are associated with transcriptional repression.
The combined disruption of multiple independent molecular machineries may result in either increased overall efficacy or unexpected phenotypic outcomes, depending on the context.
This reality argues strongly for the use of chemical probes to validate WDR domain targets using appropriate disease models in order to explore potential therapeutic windows — The presence of WDR repeat proteins in diverse E3 ubiquitin ligase complexes, and the seminal discovery of natural small molecule ligands that bridge E3-substrate interactions in plants, raises the possibility that bi-dentate small molecules that simultaneously bind the WDR domain of the E3 and a therapeutic target protein of interest may enable the proteasome-mediated elimination of the target protein.
Indeed, thalidomide and its derivatives have been discovered to act in exactly this fashion, by bridging an ectopic interaction between the CUL4 substrate receptor subunit cereblon CRBN and the transcription factors Ikaros and Aiolos, which leads to their degradation and efficacy against B-cell malignancies , It is not clear yet whether these sulfonamide drugs bind the WDR domain or another region of DCAF15, but E3-associated WDR domains may represent interesting general alternatives to CRBN, with diverse tissue distributions and availability profiles for harnessing chemically the ubiquitin-proteasome system.
In conclusion, the ubiquitous, functionally versatile, and often disease-associated WDR domain has a structurally diverse pocketome, and is probably more druggable than meets the eye, thanks to its intrinsic conformational flexibility.
Consequently WDRs offer potential avenues to target catalytic, scaffolding and substrate or activator recognition functions of diverse enzyme complexes.
Recent encouraging results for WDR inhibitors in epigenetic regulation hold great potential but still need to be validated in the clinic.
The chemical tractability of WDR domains as a target class should be further explored, especially in areas of disease biology that have so far proven undruggable by conventional approaches.
The authors acknowledge Clarissa Jakob for her careful review of the manuscript. National Center for Biotechnology Information , U.
Nat Rev Drug Discov. Author manuscript; available in PMC Nov 1. Arrowsmith 1, 6. Cheryl H. Author information Copyright and License information Disclaimer.
Copyright notice. The publisher's final edited version of this article is available at Nat Rev Drug Discov. See other articles in PMC that cite the published article.
Supp Table 2. Abstract Antagonism of protein-protein interactions PPIs with small molecules is becoming more feasible as a therapeutic approach.
Introduction Protein-protein interactions PPIs are essential mediators of both physiologic and pathologic biology, yet, until recently have been considered very challenging to target therapeutically with small molecules.
WDR domains are ubiquitous and disease-associated The blades of a WDR domain each contain a conserved glycine-histidine and tryptophan-aspartate WD motif.
Open in a separate window. Figure 1. Figure 2. WDR proteins perform in diverse cellular functions The number of WDR proteins associated with Reactome pathways and corresponding enrichment compared with the whole proteome are indicated.
Table 1 WDR proteins that may represent targets of interest References are provided in the text. Recruited by HIV-2 to counteract the effects of host cellular defense.
Epigenetic targets in oncology Epigenetic mechanisms are now recognized as being central to the etiology of many cancers 29 , 30 and proteins involved in chromatin mediated signaling are a promising target class for cancer therapy 31 , Figure 3.
Other oncology targets Many WDR proteins are implicated in cancer-associated cellular pathways beyond epigenetic mechanisms.
Regenerative medicine WDR proteins are promising candidate targets in the emerging field of regenerative medicine. Neurological disorders The WDR protein platelet activating factor acetylhydrolase 1b regulatory subunit 1 PAFAH1B1, also know as LIS1 is required for actin polymerization in cerebellar and hippocampal neurons, and functions with dynein to mediate coupling of the nucleus to the centrosome in neuronal migration Pharmacologically targeting WDR domains Considering that WDR domains are ubiquitous and often disease-associated, it comes as a surprise that only four WDR proteins have been targeted pharmacologically so far: human WDR5, EED, CDC20 and yeast Cdc4 24 — 26 , 89 , 90 These four published cases can be further grouped into two categories, depending on the specific location of the inhibitors.
Figure 4. Figure 5. Structural dynamics of WDR binding pockets Conformational rearrangement of a few side-chains can induce dramatic changes in the volume and enclosure of the central pockets of WDR5 a—c or EED d—f.
The merits of targeting a protein interaction domain Considering their ubiquitous nature, disease association, structural diversity and encouraging druggability, it is surprising that WDRs have so far been largely neglected by the drug discovery community.
Supplementary Material Supp Table 1 Click here to view. Supp Table 2 Click here to view. References 1.
Deeks ED. Venetoclax: First Global Approval. Roberts AW, et al. N Engl J Med. Shangary S, Wang S.
Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy.
Annu Rev Pharmacol Toxicol. Vassilev LT, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.
Delmore JE, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Filippakopoulos P, et al.
Selective inhibition of BET bromodomains. Shi J, Vakoc CR. The mechanisms behind the therapeutic activity of BET bromodomain inhibition.
Mol Cell. The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability.
Nat Protoc. Affinity selection-mass spectrometry screening techniques for small molecule drug discovery.
Curr Opin Chem Biol. Clark MA, et al. Design, synthesis and selection of DNA-encoded small-molecule libraries. Nat Chem Biol. Pearce NM, et al.
A multi-crystal method for extracting obscured crystallographic states from conventionally uninterpretable electron density.
Nat Commun. Lea WA, Simeonov A. Fluorescence polarization assays in small molecule screening. Expert Opin Drug Discov. Unclosed beta-propellers display stable structures: implications for substrate access to the active site of prolyl oligopeptidase.
J Mol Biol. Prolyl oligopeptidase: an unusual beta-propeller domain regulates proteolysis. WD40 proteins propel cellular networks.
Trends Biochem Sci. Margueron R, et al. Role of the polycomb protein EED in the propagation of repressive histone marks. Migliori V, et al.
Symmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenance.
Nat Struct Mol Biol. Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase. Wang Y, et al.
Nucleic Acids Res. A method for WD40 repeat detection and secondary structure prediction. PLoS One.
The many blades of the beta-propeller proteins: conserved but versatile. Here you will find dashcam firmware updates.
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Horst-Günter Marx. The stabilator area was increased, as well. In , the marketing name was changed from "" to "Charger". In , it was changed again to "Pathfinder".
Production of the Pathfinder continued until No models were built. In , the aircraft was given the Piper tapered wing and the name was changed again, this time to Dakota.
In , the company filled in the bottom end of the line with the Cherokee PA , which was designed for training and initially shipped with only two seats.
This aircraft featured a constant-speed propeller and retractable landing gear and was powered by a horsepower kW Lycoming IOB1E engine.
A hp kW version powered by a Lycoming IOC1C was offered as an option beginning in and designated the PAR; the hp model was dropped after The Arrow II came out in , featuring a five-inch fuselage stretch to increase legroom for the rear-seat passengers.
It also featured larger fuel tanks, increasing capacity from 50 to 77 gallons. A three-bladed propeller was optional.
Although the plane kept the designation, it was, in fact, a hp plane and was shipped mainly as a four-seat version. In , the Cherokee was named the Cherokee Challenger and had its fuselage lengthened slightly and its wings widened and the Cherokee was named the Charger with similar airframe modifications.
Piper reintroduced the Cherokee in , renaming it the Cherokee Warrior PA and giving it the Archer's stretched body and a new, semi-tapered wing.
In , Piper stopped producing the Cruiser and Pathfinder , but introduced a new hp kW plane, the Dakota PA , based on the Cherokee , Charger and Pathfinder models, but with the new semi-tapered wing.
The aircraft did not sell well and production ended in This aircraft had slightly improved aerodynamic wheel fairings introduced in Later models of the Warrior II, manufactured after July , incorporated a gross weight increase to 2, pounds, giving a useful load over pounds.
This same aircraft, now available with a glass cockpit , was available as the Warrior III and was marketed as a training aircraft. It featured a lengthened fuselage and seating for one pilot and five passengers.
Chincul S. By September , 20 Dakotas had been assembled in Chile. The original Piper Aircraft company declared bankruptcy in In , the New Piper Aircraft company was created.
It was renamed Piper Aircraft once again in Originally, all Cherokees had a constant-chord , rectangular planform wing, popularly called the " Hershey Bar " wing because of its resemblance to the convex, rectangular chocolate bar.
Beginning with the Warrior in , Piper switched to a semi-tapered wing with the NACA profile and a 2-foot-longer 0.
The constant chord is maintained from the root to mid-wing, at which point a tapered section sweeping backwards on the leading edge continues until the tip.
Both Cherokee wing variants have an angled wing root; i. Debate is ongoing about the relative benefits of the two wing shapes.
According to the Cherokee's lead designer, Fred Weick , the semi-tapered wing was introduced to "improve stall characteristics and increase wingspan," and side-by-side testing of the two shapes found that with the semitapered wing, "the plane had better climb and flatter flight characteristics"  The original version of the wing had a structural weakness that caused a structural failure during an aerobatic maneuver, but that was fixed for all later wings.
Aviation journalist Peter Garrison is also in the Hershey-bar wing camp, claiming that the semitapered shape has a neutral effect on drag: "to prevent tip stall, designers have resorted to providing the outboard portions of tapered wings with more cambered airfoil sections, drooped or enlarged leading edges, fixed or automatic leading edge slots or slats and most commonly, wing twist or "washout".
The trouble with these fixes is that they all increase the drag, cancelling whatever benefit the tapered wing was supposed to deliver in the first place.
For the Cherokee family, Piper used their traditional flight-control configuration. The horizontal tail is a stabilator with an antiservo tab sometimes termed an antibalance tab.Conformational rearrangement think, so undercover stream hd filme phrase a few side-chains can induce dramatic changes in the volume and enclosure of the central pockets of WDR5 a—c or EED d—f. O camera extrem de buna mai ales pentru acest pret. Pana la urma asta ar fi roul unui gps, viteza si locatie. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros erasmus orgasmus. Lea WA, Simeonov A. However, allosteric inhibitors targeting the WDR subunit, EED 25 lindsay mills, 26retain on-target inhibition in cells resistant to catalytic inhibitors. Aviation journalist Peter Garrison is also in the Hershey-bar wing wdr 161, claiming that the semitapered shape has a neutral effect on drag: "to prevent tip stall, designers have resorted to providing check this out outboard portions of tapered wings with more cambered airfoil sections, drooped or enlarged leading edges, fixed or automatic leading edge slots or slats and most commonly, wing twist or "washout". Este o alegere foarte buna la acest pret. Produse recomandate Scurta descriere Comparare Detalii tehnice Review-uri.
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