A recent study published in Nature by Radko-Juettner and colleagues reports an unexpected mutant-specific synthetic lethality in which the E3 protein ubiquitin ligase DCAF5 specifically degrades mutant but not wild-ty...A recent study published in Nature by Radko-Juettner and colleagues reports an unexpected mutant-specific synthetic lethality in which the E3 protein ubiquitin ligase DCAF5 specifically degrades mutant but not wild-type SWI/SNF chromatin remodeling complexes.1 DCAF5 contains a likely druggable WDR domain,providing a new avenue for the development of novel therapeutics for aggressive cancers with SMARCB1 loss of function mutations.展开更多
The WD40 domain exhibits aβ-propeller architecture,often comprising seven blades.The WD40 domain is one of the most abundant domains and also among the top interacting domains in eukaryotic genomes.In this review,we ...The WD40 domain exhibits aβ-propeller architecture,often comprising seven blades.The WD40 domain is one of the most abundant domains and also among the top interacting domains in eukaryotic genomes.In this review,we will discuss the identification,definition and architecture of the WD40 domains.WD40 domain proteins are involved in a large variety of cellular processes,in which WD40 domains function as a protein-protein or protein-DNA interaction platform.WD40 domain mediates molecular recognition events mainly through the smaller top surface,but also through the bottom surface and sides.So far,no WD40 domain has been found to display enzymatic activity.We will also discuss the different binding modes exhibited by the large versatile family of WD40 domain proteins.In the last part of this review,we will discuss how post-translational modifications are recognized by WD40 domain proteins.展开更多
The co-translational targeting or insertion of secretory and membrane proteins into the endoplasmic reticulum （ER） is a key biological process mediated by the signal recognition particle （SRP）. In eukaryotes, the ...The co-translational targeting or insertion of secretory and membrane proteins into the endoplasmic reticulum （ER） is a key biological process mediated by the signal recognition particle （SRP）. In eukaryotes, the SRP68-SRP72 （SRP68/72） heterodimer plays an essen- tial role in protein translocation. However, structural information on the two largest SRP proteins, SRP68 and SRP72, is limited, espe- cially regarding their interaction. Herein, we report the first crystal structures of human apo-SRP72 and the SRP68/72 complex at 2.91A. and 1.7A resolution, respectively. The SRP68-binding domain of SRP72 contains four atypical tetratricopeptide repeats （TPR） and a flexible C-terminal cap. Apo-SRP72 exists mainly as dimers in solution. To bind to SRP68, the SRP72 homodimer disassociates, and the indispensable C-terminal cap undergoes a pronounced conformational change to assist formation of the SRP68/72 heterodi- mer. A 23-residue polypeptide of SRP68 is sufficient for tight binding to SRP72 through its unusually hydrophobic and extended sur- face. Structural, biophysical, and mutagenesis analyses revealed that cancer-associated mutations disrupt the SRP68-SRP72 interaction and their co-localization with ER in mammalian cells. The results highlight the essential role of the SRP68-SRP72 inter- action in SRP-mediated protein translocation and provide a structural basis for disease diagnosis, pathophysiology, and drug design.展开更多
The cofactor nicotinamide adenine dinucleotide(NAD+)plays a key role in a wide range of physiological processes and maintaining or enhancing NAD+levels is an established approach to enhancing healthy aging.Recently,se...The cofactor nicotinamide adenine dinucleotide(NAD+)plays a key role in a wide range of physiological processes and maintaining or enhancing NAD+levels is an established approach to enhancing healthy aging.Recently,several classes of nicotinamide phosphoribosyl transferase(NAMPT)activators have been shown to increase NAD+levels in vitro and in vivo and to demonstrate beneficial effects in animal models.The best validated of these compounds are structurally related to known urea-type NAMPT inhibitors,however the basis for the switch from inhibitory activity to activation is not well understood.Here we report an evaluation of the structure activity relationships of NAMPT activators by designing,synthesising and testing compounds from other NAMPT ligand chemotypes and mimetics of putative phosphoribosylated adducts of known activators.The results of these studies led us to hypothesise that these activators act via a through-water interaction in the NAMPT active site,resulting in the design of the first known urea-class NAMPT activator that does not utilise a pyridine-like warhead,which shows similar or greater activity as a NAMPT activator in biochemical and cellular assays relative to known analogues.展开更多
Protein arginine methyltransferases(PRMTs)are attractive targets for developing therapeutic agents,but selective PRMT inhibitors targeting the cofactor SAM binding site are limited.Herein,we report the discovery of a ...Protein arginine methyltransferases(PRMTs)are attractive targets for developing therapeutic agents,but selective PRMT inhibitors targeting the cofactor SAM binding site are limited.Herein,we report the discovery of a noncanonical but less polar SAH surrogate YD1113 by replacing the benzyl guanidine of a pan-PRMT inhibitor with a benzyl urea,potently and selectively inhibiting PRMT3/4/5.Importantly,crystal structures reveal that the benzyl urea moiety of YD1113 induces a unique and novel hydrophobic binding pocket in PRMT3/4,providing a structural basis for the selectivity.In addition,YD1113 can be modified by introducing a substrate mimic to form a“T-shaped”bisubstrate analogue YD1290 to engage both the SAM and substrate binding pockets,exhibiting potent and selective inhibition to typeⅠPRMTs(IC_(50)<5 nmol/L).In summary,we demonstrated the promise of YD1113 as a general SAH mimic to build potent and selective PRMT inhibitors.展开更多
基金German translational cancer network(DKTK),the Frankfurt Cancer Institute(FCI)German Cancer Aid(Krebshilfe)grant TACTIC and the SFB1430(Molecular Mechanisms of Cell State Transitions)。
文摘A recent study published in Nature by Radko-Juettner and colleagues reports an unexpected mutant-specific synthetic lethality in which the E3 protein ubiquitin ligase DCAF5 specifically degrades mutant but not wild-type SWI/SNF chromatin remodeling complexes.1 DCAF5 contains a likely druggable WDR domain,providing a new avenue for the development of novel therapeutics for aggressive cancers with SMARCB1 loss of function mutations.
基金This research was supported by the Structural Genomics Consortium,a registered charity(No.1097737)that receives funds fromthe Canadian Institutes for Health Research,the Canadian Foundation for Innovation,Genome Canada through the Ontario GenomicsInstitute,Glaxo Smith Kline,Karolinska Institutet,the Knut and Alice Wallenberg Foundation,the Ontario lnnovation Trust,the Ontario Ministry for Research and Innovation,Merck&Co.,Inc.,the Novartis Research Foundation,the Swedish Agency for Innovation Systems,the Swedish Foundation for Strategic Research and the Wellcome Trust.
文摘The WD40 domain exhibits aβ-propeller architecture,often comprising seven blades.The WD40 domain is one of the most abundant domains and also among the top interacting domains in eukaryotic genomes.In this review,we will discuss the identification,definition and architecture of the WD40 domains.WD40 domain proteins are involved in a large variety of cellular processes,in which WD40 domains function as a protein-protein or protein-DNA interaction platform.WD40 domain mediates molecular recognition events mainly through the smaller top surface,but also through the bottom surface and sides.So far,no WD40 domain has been found to display enzymatic activity.We will also discuss the different binding modes exhibited by the large versatile family of WD40 domain proteins.In the last part of this review,we will discuss how post-translational modifications are recognized by WD40 domain proteins.
文摘The co-translational targeting or insertion of secretory and membrane proteins into the endoplasmic reticulum （ER） is a key biological process mediated by the signal recognition particle （SRP）. In eukaryotes, the SRP68-SRP72 （SRP68/72） heterodimer plays an essen- tial role in protein translocation. However, structural information on the two largest SRP proteins, SRP68 and SRP72, is limited, espe- cially regarding their interaction. Herein, we report the first crystal structures of human apo-SRP72 and the SRP68/72 complex at 2.91A. and 1.7A resolution, respectively. The SRP68-binding domain of SRP72 contains four atypical tetratricopeptide repeats （TPR） and a flexible C-terminal cap. Apo-SRP72 exists mainly as dimers in solution. To bind to SRP68, the SRP72 homodimer disassociates, and the indispensable C-terminal cap undergoes a pronounced conformational change to assist formation of the SRP68/72 heterodi- mer. A 23-residue polypeptide of SRP68 is sufficient for tight binding to SRP72 through its unusually hydrophobic and extended sur- face. Structural, biophysical, and mutagenesis analyses revealed that cancer-associated mutations disrupt the SRP68-SRP72 interaction and their co-localization with ER in mammalian cells. The results highlight the essential role of the SRP68-SRP72 inter- action in SRP-mediated protein translocation and provide a structural basis for disease diagnosis, pathophysiology, and drug design.
基金funded by the China Sponsorship Council(No.201709110169)support by the SGC,a registered charity(number 1097737)that receives funds from AbbVie,Bayer Pharma AG,Boehringer Ingelheim,Canada Foundation for Innovation,Eshelman Institute for Innovation,Genome Canada,Innovative Medicines Initiative(EU/EFPIA),Janssen,Merck KGaA Darmstadt Germany,MSD,Novartis Pharma AG,Ontario Ministry of Economic Development and Innovation,Pfizer,S?o Paulo Research Foundation-FAPESP and Takeda+2 种基金supported by the Frankfurt Cancer Institute(FCI)the DKTK translational cancer networkfinancial support by the European Union Horizon 2020 research and innovation program under grant agreement number 730872,project CALIPSOplus。
文摘The cofactor nicotinamide adenine dinucleotide(NAD+)plays a key role in a wide range of physiological processes and maintaining or enhancing NAD+levels is an established approach to enhancing healthy aging.Recently,several classes of nicotinamide phosphoribosyl transferase(NAMPT)activators have been shown to increase NAD+levels in vitro and in vivo and to demonstrate beneficial effects in animal models.The best validated of these compounds are structurally related to known urea-type NAMPT inhibitors,however the basis for the switch from inhibitory activity to activation is not well understood.Here we report an evaluation of the structure activity relationships of NAMPT activators by designing,synthesising and testing compounds from other NAMPT ligand chemotypes and mimetics of putative phosphoribosylated adducts of known activators.The results of these studies led us to hypothesise that these activators act via a through-water interaction in the NAMPT active site,resulting in the design of the first known urea-class NAMPT activator that does not utilise a pyridine-like warhead,which shows similar or greater activity as a NAMPT activator in biochemical and cellular assays relative to known analogues.
基金support from NIH P30 CA023168(Purdue University Center for Cancer Research)the NSERC grant(RGPIN-2021-02728(Jinrong Min)).
文摘Protein arginine methyltransferases(PRMTs)are attractive targets for developing therapeutic agents,but selective PRMT inhibitors targeting the cofactor SAM binding site are limited.Herein,we report the discovery of a noncanonical but less polar SAH surrogate YD1113 by replacing the benzyl guanidine of a pan-PRMT inhibitor with a benzyl urea,potently and selectively inhibiting PRMT3/4/5.Importantly,crystal structures reveal that the benzyl urea moiety of YD1113 induces a unique and novel hydrophobic binding pocket in PRMT3/4,providing a structural basis for the selectivity.In addition,YD1113 can be modified by introducing a substrate mimic to form a“T-shaped”bisubstrate analogue YD1290 to engage both the SAM and substrate binding pockets,exhibiting potent and selective inhibition to typeⅠPRMTs(IC_(50)<5 nmol/L).In summary,we demonstrated the promise of YD1113 as a general SAH mimic to build potent and selective PRMT inhibitors.
