Molecular basis for histone H2B ubiquitination by Bre1 E3 ligase--《第十一次全国基因功能与表观遗传调控学术研讨会摘要集》2015年
Molecular basis for histone H2B ubiquitination by Bre1 E3 ligase
【摘要】：正Histone H2B ubiquitination plays an important role in gene transcription,DNA damage repair,stem cell differentiation and many other cellular processes.The biochemical mechanism of H2B ubiquitination has been extensively studied,however the underlying structural and molecular details
【作者单位】：
【分类号】：Q75【正文快照】：
Histone H2B ubiquitination plays an important role in gene transcription,DNA damage repair,stemcell differentiation and many other cellular processes.The biochemical mechanism of H2Bubiquitination has been extensively studied,however the underlying struc
欢迎：、、)
支持CAJ、PDF文件格式，仅支持PDF格式
【相似文献】
中国期刊全文数据库
;[J];Acta Biochimica et Biophysica S2007年02期
Anjana MGowhar SNishat AAkka J;[J];遗传学报;2009年02期
PaolaGStefaniaDiMPhillipJMichelePChristianSteinkü;[J];Cell R2007年03期
Matthias O;[J];World Journal of Biological C2010年05期
WANG WCAI RXIAO HZHENG L;[J];Wuhan University Journal of Natural S2014年01期
;[J];Cell R2006年05期
Ping CJicheng ZGuohong Li;;[J];Journal of Genetics and G2013年07期
;[J];Acta Biochimica et Biophysica S2007年03期
Lianyu YXuncheng LMing LSongguang YKeqiang Wu;;[J];Journal of Integrative Plant B2013年10期
;[J];遗传学报;2012年08期
中国重要会议论文全文数据库
陈忠周;;[A];第二届全国“跨学科蛋白质研究”学术讨论会论文集[C];2008年
;[A];2011年全国药物化学学术会议——药物的源头创新论文摘要集[C];2011年
;[A];中华医学会第十七次全国儿科学术大会论文汇编（下册）[C];2012年
;[A];第十三届全国植物基因组学大会论文集[C];2012年
蒋晟;;[A];天然产物全合成—青年学术研讨会论文摘要[C];2012年
Ruiming Xu;;[A];生命的分子机器及其调控网络——2012年全国生物化学与分子生物学学术大会摘要集[C];2012年
Sheng JYiwu YZhenchao Tu;;[A];第八届全国化学生物学学术会议论文摘要集[C];2013年
Feng TLu HSu HYang Bo;You Q;[A];2012长三角药物化学研讨会论文集[C];2012年
;[A];上海市植物生理学会成立三十周年庆祝活动暨第三届上海市植物生理学青年学术研讨会论文集[C];2009年
Hao Hu;Chao-Pei LChaoyang XMingzhu WNa YGuohong Li;Rui-Ming Xu;;[A];第四届中国结构生物学学术讨论会论文摘要集[C];2013年
&快捷付款方式
&订购知网充值卡
400-819-9993
《中国学术期刊（光盘版）》电子杂志社有限公司
同方知网数字出版技术股份有限公司
地址：北京清华大学 84-48信箱 大众知识服务
出版物经营许可证 新出发京批字第直0595号
订购热线：400-819-82499
服务热线：010--
在线咨询：
传真：010-
京公网安备75号Inhibitors | Activators | Antagonists (8)water-soluble
Product Name
Information
Product Use Citation
Customer Product Validation
Nutlin-3 is a potent and selective Mdm2 (RING finger-dependent ubiquitin protein ligase for itself and p53) antagonist with IC50 of 90 nM in a cell- stabilizes p73 in p53-deficient cells.
Hepatology, ):
Mol Ther, ):857-65
Int J Cancer, 2/ijc.29194
JNJ- (Serdemetan) acts as a HDM2 ubiquitin ligase antagonist and also induces early apoptosis in p53 wild-type cells, inhibits cellular proliferation followed by delayed apoptosis in the absence of functional p53. Phase 1.
Sci Rep, 4
Mol Ther, ):857-65
Head Neck, 2/hed.23822
Thalidomide was introduced as a sedative drug, immunomodulatory agent and also is investigated for treating symptoms of many cancers. Thalidomide inhibits an E3 ubiquitin ligase, which is a CRBN-DDB1-Cul4A complex.
FASEB J, ):4829-39
NSC 207895 suppresses MDMX with IC50 of 2.5 μM, leading to enhanced p53 stabilization/activation and DNA damage, and also regulates MDM2, an E3 ligase.
Tosyl-L-Arginine Methyl Ester (TAME) is an APC inhibitor.
AT406 (SM-406, ARRY-334543) is a potent Smac mimetic and an antagonist of IAP (inhibitor of apoptosis protein via E3 ubiquitin ligase), binding to XIAP-BIR3, cIAP1-BIR3 and cIAP2-BIR3 with Ki of 66.4 nM, 1.9 nM, and 5.1 nM, 50- to 100-fold higher affinities than the Smac AVPI peptide. Phase 1.
Cancer Res, 8/.CAN-14-2199
Int J Oncol, 2/ijo.. Epub 2016 May 16
Biochem Biophys Res Commun, ):293-9
RITA (NSC 652287) induces both DNA-protein and DNA-DNA cross-links with no detectable DNA single-strand breaks, and also inhibits MDM2-p53 interaction by targeting p53.
Nat Chem Biol, 8/nchembio.1986
Oncogene, 8/onc.2014.37
Tenovin-1 protects against MDM2-mediated p53 degradation, which involves ubiquitination, and acts through inhibition of protein-deacetylating activities of SirT1 and SirT2.
Hover Mouse over '+' to display IC50
Product Name
Solubility (25°C)
Tags: Ubiquitin ligase inhibitor | E3 ligase inhibitor
E-newsletter
Get updates, discounts and special offers
Your information is safe with us.
Unconditional Return & Replacement Policy
On All Orders over $500
Tel: +1-832-582-8158
Fax: +1-832-582-8590
Tel: +49-89-
Fax: +49-89-
Other Countries & RegionsFrom Wikipedia, the free encyclopedia
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2
that has been loaded with , recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. The
is attached to a
on the target protein by an . E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the . However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of , as well as
proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.
In , an ubiquitin-protein ligase ( ) is an
ATP + ubiquitin + protein lysine
{\displaystyle \rightleftharpoons }
AMP + diphosphate + protein N-ubiquityllysine
of this enzyme are , , and a , whereas its 3
are , , and protein N-ubiquityllysine. Canonical ubiquitylation creates an isopeptide bond between a lysine residue on a target protein and the ubiquitin C-terminal Glycine 76.
This enzyme belongs to the family of , to be specific those forming carbon-nitrogen bonds as acid-D-amino-acid ligases (peptide synthases). The
of this enzyme class is ubiquitin:protein-lysine N-ligase (AMP-forming). This enzyme is also called ubiquitin-activating enzyme. This enzyme participates in 3 : , , and .[]
Schematic diagram of the ubiquitylation system.
The ubiquitin ligase is referred to as an E3, and operates in conjunction with an
and an . There is one major E1 enzyme, shared by all ubiquitin ligases, that uses
to activate
and transfers it to an E2 enzyme. The E2 enzyme interacts with a specific E3 partner and transfers the
to the target . The E3, which may be a , is, in general, responsible for targeting ubiquitination to specific
proteins.[]
The ubiquitylation reaction proceeds in three or four steps depending on the mechanism of action of the E3 ubiquitin ligase. In the conserved first step, an E1
residue attacks the ATP-activated C-terminal glycine on ubiquitin, resulting in a
Ub-S-E1 complex. The energy from ATP and diphosphate hydrolysis drives the formation of this reactive thioester, and subsequent steps are thermoneutral. Next, a transthiolation reaction occurs, in which an E2 cysteine residue attacks and replaces the E1.
type E3 ligases will have one more transthiolation reaction to transfer the ubiquitin molecule onto the E3, whereas the much more common
type ligases transfer ubiquitin directly from E2 to the substrate. The final step in the first ubiquitylation event is an attack from the target protein lysine amine group, which will remove the cysteine, and form a stable isopeptide bond. One notable exception to this is
protein, which appears to be ubiquitylated using its N-terminal amine, thus forming a peptide bond with ubiquitin.
Humans have an estimated 500-1000 E3 ligases, which impart substrate specificity onto the E1 and E2. The E3 ligases are classified into four families: HECT, RING-finger, U-box, and PHD-finger. The RING-finger E3 ligases are the largest family and contain ligases such as the
(APC) and the
(--F-box protein complex). SCF complexes consist of four proteins: Rbx1, Cul1, Skp1, which are invariant among SCF complexes, and an F-box protein, which varies. Around 70 human F-box proteins have been identified. F-box proteins contain an F-box, which binds the rest of the SCF complex, and a substrate binding domain, which gives the E3 its substrate specificity.
Ubiquitin with lysine residues (red), C-terminal methionine (blue), and N-terminal glycine (yellow).
Ubiquitin signaling relies on the diversity of ubiquitin tags for the specificity of its message. A protein can be tagged with a single ubiquitin molecule (monoubiquitylation), or variety of different chains of ubiquitin molecules (polyubiquitylation). E3 Ubiquitin ligases catalyze polyubiquitination events much in the same way as the single ubiquitylation mechanism, using instead a lysine residue from a ubiquitin molecule currently attached to substrate protein to attack the C-terminus of a new ubiquitin molecule. For example, a common 4-ubiquitin tag, linked through the lysine at position 48 (K48) recruits the tagged protein to the proteasome, and subsequent degradation. However, all seven of the ubiquitin lysine residues (K6, K11, K27, K29, K48, and K63), as well as the C-terminal methionine are used in chains in vivo.
Monoubiquitination has been linked to membrane protein
pathways. For example, phosphorylation of the Tyrosine at position 1045 in the
(EGFR) can recruit the RING type E3 ligase c-Cbl, via an . C-Cbl monoubiquitylates EGFR, signaling for its internalization and trafficking to the lysosome.
Monoubiquitination also can regulate cytosolic protein localization. For example, the E3 ligase
ubiquitylates
either for degradation (K48 polyubiquitin chain), or for nuclear export (monoubiquitylation). These events occur in a concentration dependent fashion, suggesting that modulating E3 ligase concentration is a cellular regulatory strategy for controlling protein homeostasis and localization.
E3 ubiquitin ligases regulate homeostasis, cell cycle, and DNA repair pathways, and as a result, a number of these proteins are involved in a variety of cancers, including famously MDM2, , and . For example, a mutation of MDM2 has been found in , , and
(amongst others) to deregulate MDM2 concentrations by increasing its promoter’s affinity for the , causing increased transcription of MDM2 mRNA.
(Really Interesting New Gene) domain binds the E2 conjugase and might be found to mediate enzymatic activity in the E2-E3 complex
An F-box domain (as in the SCF complex) binds the ubiquitinated substrate. (e.g., Cdc 4, which binds Grr1, which binds Cln).
A , which is involved in the transfer of ubiquitin from the E2 to the substrate.
/ BC-box/ eloBC/ /
Dou H, Buetow L, Hock A, Sibbet GJ, Vousden KH, Huang DT (Feb 2012). . Nature Structural & Molecular Biology. 19 (2): 184–92. :.  .  .
Hershko A, Ciechanover A (1998). "The ubiquitin system". Annual Review of Biochemistry. 67: 425–79. :.  .
Teixeira LK, Reed SI (2013). "Ubiquitin ligases and cell cycle control". Annual Review of Biochemistry. 82: 387–414. :.  .
Li W, Bengtson MH, Ulbrich A, Matsuda A, Reddy VA, Orth A, Chanda SK, Batalov S, Joazeiro CA (2008). . PLOS ONE. 3 (1): e1487. :. :.  .  .
Walsh, Christopher (2006). Posttranslational Modification of Proteins: Expanding Nature's Inventory. Englewood, CO: Roberts.  .[]
Metzger MB, Hristova VA, Weissman AM (Feb 2012). . Journal of Cell Science. 125 (Pt 3): 531–7. :.  .  .
Bloom J, Amador V, Bartolini F, DeMartino G, Pagano M (Oct 2003). "Proteasome-mediated degradation of p21 via N-terminal ubiquitinylation". Cell. 115 (1): 71–82. :.  .
Nakayama KI, Nakayama K (May 2006). "Ubiquitin ligases: cell-cycle control and cancer". Nature Reviews. Cancer. 6 (5): 369–81. :.  .
Jin J, Cardozo T, Lovering RC, Elledge SJ, Pagano M, Harper JW (Nov 2004). . Genes & Development. 18 (21): 2573–80. :.  .  .
Vijay-Kumar, S.; Bugg, C. E.; Cook, W. J. (1987). "Structure of ubiquitin refined at 1.8 A resolution". J. Mol. Biol. 194: 531–44. :.  .
Behrends C, Harper JW (May 2011). "Constructing and decoding unconventional ubiquitin chains". Nature Structural & Molecular Biology. 18 (5): 520–8. :.  .
Bonifacino JS, Traub LM (2003). "Signals for sorting of transmembrane proteins to endosomes and lysosomes". Annual Review of Biochemistry. 72: 395–447. :.  .
Li M, Brooks CL, Wu-Baer F, Chen D, Baer R, Gu W (Dec 2003). "Mono- versus polyubiquitination: differential control of p53 fate by Mdm2". Science. 302 (5652): 1972–5. :. :.  .
Lipkowitz S, Weissman AM (Sep 2011). . Nature Reviews. Cancer. 11 (9): 629–43. :.  .  .
Hou YC, Deng JY (Jan 2015). . World Journal of Gastroenterology. 21 (3): 786–93. :10.3748/wjg.v21.i3.786 (inactive ).  .  .
de Martino M, Taus C, Wessely IS, Lucca I, Hofbauer SL, Haitel A, Shariat SF, Klatte T (Feb 2015). "The T309G Murine Double Minute 2 Gene Polymorphism Is an Independent Prognostic Factor for Patients with Renal Cell Carcinoma". DNA and Cell Biology. 34 (2): 107–12. :.  .
Tang T, Song X, Yang Z, Huang L, Wang W, Tan H (Nov 2014). "Association between murine double minute 2 T309G polymorphism and risk of liver cancer". Tumour Biology. 35 (11): 11353–7. :.  .
Ardley HC, Robinson PA (2005). "E3 ubiquitin ligases". Essays in Biochemistry. 41: 15–30. :.  .
Bai C, Sen P, Hofmann K, Ma L, Goebl M, Harper JW, Elledge SJ (Jul 1996). "SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box". Cell. 86 (2): 263–74. :.  .
at the US National Library of Medicine
: CO CS and CN
( 6.1-6.3)
: Hidden categories:Ubiquitin modification of substrate proteins is achieved by the activity of E1 activating, E2 conjugating and E3 ligase enzymes. Substrate proteins can be modified with one (mono-ubiquitination) or many (poly-ubiquitination) molecules of ubiquitin, and each type of modification has distinct regulatory fates.
E3 ligases number in the thousands and have the highest level of specificity for the target protein to be modified by ubiquitin or ubiquitin-like modifiers (UBL).
In addition, many E3s have been implicated in human
disease and are attractive targets for drug discovery. However, currently no small molecule modulators for this class of enzymes have reached the clinic. Each E3 enzyme targets a small number of proteins for Ub modification but the exact substrates are mostly unknown and their identification continues to be a challenge. E3 ligase enzymes are a large (> 500) and complex super- family, many of which contain binding domains to interact with ubiquitin, E2 enzymes and substrate proteins. In addition to substrate ubiquitination, many E3 ligases can also self- or auto-ubiquitinate in the presence of an E2 enzyme, a property that may be used as an auto-regulatory mechanism to control its own intracellular levels. In general, the detailed molecular mechanism, stoichiometries and linkage site selection of E3 enzymes are poorly understood. As with ubiquitin E3 ligases, similar activities are also part of the final conjugation processes for other UBL proteins. There are E3 enzymes that are specific for targets that are modified SUMO, NEDD8, ISG15 and presumably also for FAT10 and UFM1.
Ubiquitin E3 enzymes are classified into two primary classes according to domain homology and mechanism of action. The subtypes include the HECT (homologous to E6-AP Cterminus) and RING (Really Interesting New Gene) proteins. The HECT E3 ligases contain a large domain (~ 350 residues) with a catalytic cysteine residue that transfers Ub to via a cognate E2 directly to the substrate. These enzymes interact directly with substrate target proteins to effect poly-ubiquitination. Examples of HECT proteins include the viral E6AP, ARB-BP1, Itch, NEDD4, Smurf2 and WWPI. The RING E3 ligases have two zinc ions coordinated by multiple CYS and His residues to form a globular E2-binding domain. In contrast to HECT E3s, RING E3s do not have the recognizable catalytic active sites that define “classical” enzymes. Instead, these E3s which have large binding interfaces and act as scaffold proteins that bring together the participant E2 and substrate proteins. Examples of RING-FINGER proteins include BRCA1, Cbl, Efp, Hdm2, MurF1, Parkin, SIAH, TRAF6, Rfn11 and XIAP. Two other RING-FINGER related domains, the U-box (UFD2-homology domain) and PHD (plant homeo domain) also confer E3 activity. U-box E3s (CHIP, UFD2, PRP19, UIP5, CYC4) have a similar RING-FINGER tertiary structure and may participate in protein quality control via their interaction with chaperones. PHD containing proteins (c- MIR, AIRE, MR1, MR2) have E3 activity that is PHD domain-dependent but it is not known if all PHD proteins function similarly. Another group of E3s are multi-component complexes such as the modular SCF (Skp1/Cullin/F-box/Rbx1/2) family. These complexes are exemplified by the Rbx RING-FINGER E3 Ligase Enzymes proteins in various combinations with at least three components including a Cullin protein, an adaptor (Sk1, Elongin B/C or a BTB) and a substrate binding protein (Fbox, SOCS or BTB). The APC (anaphase-promoting complex) is also a large multiprotein- E3 complex that regulates both entry and exit from mitosis via the ubiquitination of key cell cycle regulators such as cyclin B, and securin. This large complex (~ 11 subunits) is
similar to SCF and contains a catalytic core cullin (Apc2) and a RING protein (Apc11).
E3 ligases confer specificity to ubiquitination by recognizing target substrates and mediating transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to substrate. The activity of most E3s is specified by a RING domain, which binds to an E2 approximately ubiquitin thioester and activates discharge of its ubiquitin cargo. E2-E3 complexes can either mono-ubiquitinate a substrate lysine or synthesize poly-ubiquitin chains assembled via different lysine residues of ubiquitin. These modifications can have diverse effects on the substrate, ranging from proteasome-dependent proteolysis to modulation of protein function, structure, assembly, and/or localization. Not surprisingly, RING E3-mediated ubiquitination can be regulated in a number of ways. RING-based E3s are specified by over 600 human genes, surpassing the 518 protein kinase genes. Accordingly, RING E3s have been linked to the control of many cellular processes and to multiple human diseases. Despite their critical importance, our knowledge of the physiological partners, biological functions, substrates, and mechanism of action for most RING E3s remains at a rudimentary stage.
Accessory Proteins
Human Recombinant
50 ug, 100 ug
Human Recombinant
Viral Recombinant
Human Recombinant
Human Recombinant
Human Recombinant
T. castaneum Recombinant
Activity Kits
Human Recombinant
Human Recombinant
Human Recombinant
Human Recombinant
Human Recombinant
Human Recombinant
Human Recombinant
human recombinant
Human Recombinant
Human Recombinant
Human Recombinant
Human Recombinant
Human Recombinant
Human Recombinant
Human Recombinant
Human Recombinant
Human Recombinant
Human Recombinant
Human Recombinant
E. coli Recombinant
Human Recombinant
Inhibitors
Category Menu}