Eukaryotic translation initiation factor 2B (eIF2B) is the guanine nucleotide exchange factor (GEF) for eukaryotic translation initiation factor 2, which stimulates formation of the eIF2-GTP-Met-tRNA i Met ternary complex (TC) in a manner inhibited by phosphorylated eIF2 [eIF2(␣P)]. While eIF2B contains five subunits, the /Gcd6 subunit is sufficient for GEF activity in vitro. The ␦/Gcd2 and ␤/Gcd7 subunits function with ␣/Gcn3 in the eIF2B regulatory subcomplex that mediates tight, inhibitory binding of eIF2(␣P)-GDP, but the essential functions of ␦/Gcd2 and ␤/Gcd7 are not well understood. We show that the depletion of wild-type ␤/Gcd7, three lethal ␤/Gcd7 amino acid substitutions, and a synthetically lethal combination of substitutions in ␤/Gcd7 and eIF2␣ all impair eIF2 binding to eIF2B without reducing /Gcd6 abundance in the native eIF2B-eIF2 holocomplex. Additionally, ␤/Gcd7 mutations that impair eIF2B function display extensive allele-specific interactions with mutations in the S1 domain of eIF2␣ (harboring the phosphorylation site), which binds to eIF2B directly. Consistent with this, ␤/Gcd7 can overcome the toxicity of eIF2(␣P) and rescue native eIF2B function when overexpressed with ␦/Gcd2 or ␥/Gcd1. In aggregate, these findings provide compelling evidence that ␤/Gcd7 is crucial for binding of substrate by eIF2B in vivo, beyond its dispensable regulatory role in the inhibition of eIF2B by eIF (␣P). Initiator methionyl tRNA (Met-tRNA iMet ) is recruited to the small (40S) ribosomal subunit in the ternary complex (TC) containing activated, GTP-bound initiation factor 2 (eIF2). AUG recognition triggers the completion of GTP hydrolysis, with release of P i from eIF2-GDP-P i , insertion of Met-tRNA i Met in the ribosomal P site, and dissociation of inactive eIF2-GDP from the translation preinitiation complex. As the binary complex eIF2-GDP dissociates slowly and eIF2 binds more tightly to GDP than GTP, eIF2B is needed to recycle eIF2-GDP to eIF2-GTP for rapid reassembly of the TC. eIF2B contains five subunits (␣ through ε) well conserved between yeast and mammals and occurs in a 1:1 holocomplex with eIF2 (7, 39). Except for eIF2B␣ (encoded by GCN3), the other four eIF2B subunits are essential in yeast. Remarkably, only the C-terminal portion of ε/Gcd6 is sufficient for guanine nucleotide exchange factor (GEF) function in vitro, albeit with lower activity than for the eIF2B holocomplex (22), and contains a key catalytic residue and determinants for binding of the ␤ and ␥ subunits of eIF2 (36).Recycling of eIF2 by eIF2B is impaired by phosphorylation of eIF2 on serine 51 of its ␣ subunit. Phosphorylated eIF2 [eIF2(␣P)]-GDP is a poor substrate for nucleotide exchange and binds more tightly to eIF2B than does unphosphorylated eIF2-GDP, thus acting as a competitive inhibitor. The eIF2␣ kinase in budding yeast, Gcn2, is activated by amino acid limitation and produces eIF2(␣P) at levels that do not fully block translation initiation and that specifically increase translation of GCN4, a transcriptional activator of a...

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, the disease caused by SARS-CoV-2, has been declared as a global pandemic. Traditional medicinal plants have long history to treat viral infections. Our in silico approach suggested that unique phytocompounds such as emodin, thymol and carvacrol, and artemisinin could physically bind SARS-CoV-2 spike glycoproteins (6VXX and 6VYB), SARS-CoV-2 B.1.351 South Africa variant of Spike glycoprotein (7NXA), and even with ACE2 and prevent the SARS-CoV-2 binding to the host ACE2, TMPRSS2 and neutrapilin-1 receptors. Since Chloroquine has been looked as potential therapy against COVID-19, we also compared the binding of chloroquine and artemisinin for its interaction with spike proteins (6VXX, 6VYB) and its variant 7NXA, respectively. Molecular docking study of phytocompounds and SARS-CoV-2 spike protein was performed by using AutoDock/Vina software. Molecular dynamics (MD) simulation was performed for 50ns. Among all the phytocompounds, molecular docking studies revealed lowest binding energy of artemisinin with 6VXX and 6VYB, with E total −10.5 KJ mol −1 and −10.3 KJ mol −1 respectively. Emodin showed the best binding affinity with 6VYB with E total −8.8 KJ mol −1 and SARS-CoV-2 B.1.351 variant (7NXA) with binding energy of −6.4KJ mol −1 . Emodin showed best interactions with TMPRSS 2 and ACE2 with E total of −7.1 and −7.3 KJ mol −1 respectively, whereas artemisinin interacts with TMPRSS 2 and ACE2 with E total of −6.9 and −7.4 KJ mol −1 respectively. All the phytocompounds were non-toxic and non-carcinogenic. MD simulation showed that artemisinin has more stable interaction with 6VYB as compared to 6VXX, and hence proposed as potential phytochemical to prevent SARS-CoV-2 interaction with ACE-2 receptor.

Polo-like kinases (PLKs) belong to the serine/threonine kinase subfamily, characterized by the presence of the signature motif called Polo-box domain. PLK members studied so far have emerged as the conserved regulator of cell cycle and cell division in eukaryotes. The Polo-box domain adds diversity to PLK functions by targeting the enzyme to an array of substrates found at different sub-cellular structures for exquisite regulation of cell cycle. More than a dozen members of PLK subfamily have been identified in the eukaryotic world except in the higher plants. Despite the similarities in governing cell division, PLKs have diverse and unique functions in different organisms. This review summarizes the plethora of functions of PLK in yeast to humans. Along with its classical functions, this review also emphasizes on the role of PLKs in regulating DNA replication, repair, genome integrity, development, and morphogenesis pathways. Perturbations in PLK functions have disease implications, such as cancer in humans, and thus human PLK1 is targeted for cancer therapeutics. PLKs also play a vital role in regulating several stages of meiotic cell division. Thus, PLKs are emerging as a unique class of proteins with multiple and diverse functions in different organisms.