Abstract
14-3-3σ is an acidic homodimer protein with more than one hundred different protein partners associated with oncogenic signaling and cell cycle regulation. This review aims to highlight the crucial role of 14-3-3σ in controlling tumor growth and apoptosis and provide a detailed discussion on the structure–activity relationship and binding interactions of the most recent 14-3-3σ protein-protein interaction (PPI) modulators reported to date, which has not been reviewed previously. This includes the new fusicoccanes stabilizers (FC-NAc, DP-005), fragment stabilizers (TCF521-123, TCF521-129, AZ-003, AZ-008), phosphate-based inhibitors (IMP, PLP), peptide inhibitors (2a–d), as well as inhibitors from natural sources (85531185, 95911592). Additionally, this review will also include the discussions of the recent efforts by a different group of researchers for understanding the binding mechanisms of existing 14-3-3σ PPI modulators. The strategies and state-of-the-art techniques applied by various group of researchers in the discovery of a different chemical class of 14-3-3σ modulators for cancer are also briefly discussed in this review, which can be used as a guide in the development of new 14-3-3σ modulators in the near future.
Highlights
The 14-3-3 proteins are a group of acidic polypeptides that are highly conserved in all eukaryotic cells [1,2,3]
The 14-3-3 family comprises seven human isoforms which are named after their respective elution positions on high performance liquid chromatography (HPLC) (β-beta, ε-epsilon, γ-gamma, η-eta, σ-sigma, τ-tau, and ζ-zeta) with at least 500 partners forming protein–protein interaction (PPI) in mammalian cells [9,10,11,12]
The 14-3-3σ protein has attracted the attention of researchers as a vital target to fight against cancer growth and metastasis
Summary
The 14-3-3 proteins are a group of acidic polypeptides that are highly conserved in all eukaryotic cells [1,2,3]. The dimer form of 14-3-3 proteins is capable of binding two ligand motifs at the same time, either from the same target or from two different partners [19]. While helices H1–H4 were or Glu, that rsetapbllae cinebSoethroipnenpaonsditciloosned5sitantet,hthee 1in4te-3rm-3oσlecsutlarruicntteurraecti[o5n3s–b5et6w]e.eLn itkheeroestihdueersiisnohfeolircmes s, the dimer molecule of 1H45-3–H-39σwfeorerdmifsferaenctuinpt-hliekaepos-hfoarmpecoimnpwarhedictho tehae cbhoumndoonnoe.mFoeurr hcyodnrsoipshtislicorfesnidinueese(Lloysn4g9,ated bundles of anti-parallAerlg5h6e, lAicrge1s29(,Han1d–HTy9r1)3.0)WathHil3eafnoduHr5hhealviecebsee(nHp1ro–pHos4ed) itno vcoonltvriebuitne ttohtehedeiqmuielirbirziuamtion with the between both states These residues are believed to form hydrogen bonds with the binding peptide other monomanedr,drtihveethreemtraansinit ifnrogmfithveeophenelciocnefsorm(Hat5io–nHto9t)hefoclromsedtchonefoarmmaptihonip[5a7t].hic ligand-binding groove (Figure 2a) [53]. Er with the highly conserved hydrophobic core residues located at the dimer interface, i.e., Leu and Tyr, were found to play a crucial rule in the stabilization of the homodimer molecule and maintaining the full dimerization activity of 14-3-3σ (Figure 3) [53,58]. Studies have showed that, among all seven well-known human 14-3-3 isoforms, 14-3-3σ is the only isoform that possesses
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
