SER130 / Serodus - LARVOL DELTA

Discovery of Mangifera indica-based natural inhibitors against TEM-1 β-lactamase from Escherichia coli using machine learning approaches. (PubMed, Comput Biol Chem) - "The best-scoring ligands (LTS0215935, LTS0057337, LTS0207894, and LTS0086727) formed extensive hydrogen-bond networks with catalytic residues Ser70, Ser130, Asn132, Ser235, and Arg244...Density functional theory (DFT) analysis corroborated these findings, with HOMO-LUMO gaps indicating suitable electronic reactivity and molecular electrostatic potential maps highlighting complementarity with TEM-1 active-site residues. These results nominate M. indica scaffolds, particularly LTS0215935, as promising natural templates for next-generation β-lactamase inhibitors."

Journal

Deciphering curcumin's differential inhibition of KPC-3, L2, and CTX-M-15 β-lactamases through binding energetics and structural dynamics. (PubMed, In Silico Pharmacol) - "Our results demonstrate curcumin's strong binding affinity across all three enzymes, with particularly potent inhibition of L2 (ΔG = - 7.67 kcal/mol) driven by favorable van der Waals interactions (- 115.03 kJ/mol) and an extensive hydrogen bonding network involving catalytic residues Ser70 and Ser130...The study provides crucial molecular insights that could guide the development of curcumin-derived adjuvants to combat β-lactam resistance, bridging traditional medicine and modern drug discovery approaches to address this critical public health challenge. The online version contains supplementary material available at 10.1007/s40203-025-00421-6."

Journal • Infectious Disease

Development of a β-lactamase-based aggregation-induced emission lateral flow strip for the detection of clavulanic acid in Milk. (PubMed, Food Chem X) - "Then we investigated the recognition mechanisms of PC1 for CA and identified key contact amino acids: Ser70, Lys73, Ser130, Glu166, and Lys234...Eventually, the proposed PC1-based AIE(Bio-SA)-LFS was successfully verified in milk samples with a cut-off value of 20 ng mL-1. This study provides a powerful tool for on-site CA monitoring for the first time."

Journal

RAD18 O-GlcNAcylation promotes translesion DNA synthesis and homologous recombination repair. (PubMed, Cell Death Dis) - "Here, we report that human RAD18, can undergo O-GlcNAcylation at Ser130/Ser164/Thr468, which is important for optimal RAD18 accumulation at DNA damage sites...O-GlcNAcylated RAD18 promotes the binding of RAD51 to damaged DNA during HR and decreases CPT hypersensitivity. Our findings demonstrate a novel role of RAD18 O-GlcNAcylation in TLS and HR regulation, establishing a new rationale to improve chemotherapeutic treatment."

Journal • Immunology • Targeted Protein Degradation • CDC7 • HRD • PCNA • RAD51 • RAD51C

Machine learning and classical MD simulation to identify inhibitors against the P37 envelope protein of monkeypox virus. (PubMed, J Biomol Struct Dyn) - "The binding pocket comprises of Tyr48, Lys86, His115, Lys117, Ser130, Asn132, Trp280, Asn240, His325, Lys327 and Tyr346 forming strong hydrogen bonds and dense hydrophobic contacts with the screened analogs and is surrounded by positively charged patches...Transition from loop to β-strands (244-254 aa) in P37-Cidofovir and its analog complexes advocates the need for further investigations...Taken together, our results provide preferable understanding of molecular recognition and dynamics of ligand-bound states of P37, offering opportunities for development of new antivirals against MPXV. However, the need of in vitro and in vivo assays for confirmation of these results still persists.Communicated by Ramaswamy H. Sarma."

Journal • Machine learning • Infectious Disease

Mutagenesis and structural analysis reveal the CTX-M β-lactamase active site is optimized for cephalosporin catalysis and drug resistance. (PubMed, J Biol Chem) - "To investigate the preference of CTX-M enzymes for cephalosporins, we examined eleven active-site residues in the CTX-M-14 β-lactamase model system by alanine mutagenesis to assess the contribution of the residues to catalysis and specificity for the hydrolysis of the penicillin, ampicillin, and the cephalosporins cephalothin and cefotaxime. Key active site residues for class A β-lactamases, including Lys73, Ser130, Asn132, Lys234, Thr216, and Thr235, contribute significantly to substrate binding and catalysis of penicillin and cephalosporin substrates in that alanine substitutions decrease both k and k/K...Furthermore, we determined X-ray crystal structures for the apo-enzymes of the mutants N106A, S130A, N132A, N170A, T215A, and T235A. Surprisingly, in the structures of some mutants, particularly N106A and T235A, the changes in structure propagate from the site of substitution to other regions of the active site, suggesting that the impact of substitutions is due to..."

Journal • Infectious Disease

Inhibition of PP2A by LB100 sensitizes bladder cancer cells to chemotherapy by inducing p21 degradation. (PubMed, Cell Oncol (Dordr)) - "Our findings indicate that PP2A may serve as a potential therapeutic target in BLCA through regulating p21 stability."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • CDKN1A

Mutations responsible for the carbapenemase activity of SME-1. (PubMed, RSC Adv) - "These mutated residues are present close to active site residues such as Ser70, Lys73, Ser130, Asn132, Glu166, and Asn170, which participate in the hydrolytic reaction of β-lactam antibiotics. This is evident from the Ω-loop structure modification, which forms the wall of the active site and repositioning of residues involved in hydrolytic reactions, when present in the complex with meropenem in a stable state of MD simulation at 50 ns. Hence, Met69Cys, Glu104Tyr, Tyr105His, Ala237Ser, and Gly238Cys mutations could result in an altered active site structure, binding, and activity of SME-1 with meropenem and thus become resistantant against meropenem, which is a carbapenem."

Journal • Infectious Disease • Respiratory Diseases

Characterization of Interactions between CTX-M-15 and Clavulanic Acid, Desfuroylceftiofur, Ceftiofur, Ampicillin, and Nitrocefin. (PubMed, Int J Mol Sci) - "Cefotaximase-Munich (CTX-M) extended-spectrum beta-lactamases (ESBLs) are commonly associated with Gram-negative, hospital-acquired infections worldwide...The crystal structures revealed that Ser70 and five other residues (Lys73, Tyr105, Glu166, Ser130, and Ser237) participate in catalysis and binding of those compounds...DFC, a metabolite of ceftiofur, displayed lower entropy and higher enthalpy than ceftiofur. This finding suggests that compounds containing amine moiety (e.g., ampicillin) and the furfural moiety (e.g., ceftiofur) could hinder the hydrolytic activity of CTX-M-15."

Journal • Infectious Disease

Detailed investigation of catalytically important residues of class A β-lactamase. (PubMed, J Biomol Struct Dyn) - "Ser70, Lys73, Ser130, Glu166, and Asn170 residues are mostly conserved and have a role in the enzyme's catalytic activity. In-depth investigation of 69, 130, 131, 132, 164, 165, 166, 170, 171, 173, 176, 178, 179, 182, 237, 244, 275 and 276 residues were done along with its kinetic analysis for knowing its significance. Further, detailed information from many previous studies was gathered to know the effect of mutations on the kinetic activity of class A β-lactamase enzymes with β-lactam antibiotics.Communicated by Ramaswamy H. Sarma."

Journal • Infectious Disease

Variations in the SDN Loop of Class A Beta-Lactamases: A Study of the Molecular Mechanism of BlaC (Mycobacterium tuberculosis) to Alter the Stability and Catalytic Activity Towards Antibiotic Resistance of MBIs. (PubMed, Front Microbiol) - "Alterations at Ser130 in conserved SDN loop confer resistance to mechanism-based inhibitors (MBIs) commonly observed in various clinical isolates...To understand the molecular reasoning behind the unavailability of such mutation in real life, we have used circular dichroism (CD) spectroscopy, differential scanning calorimetry (DSC), molecular dynamics (MD) simulation, and stability-based enzyme activity to compare the stability and dynamic behaviors of native and S130G/A mutant form of BlaC. A significant decrease in melting temperature (BlaC T 60°C, S130A T 50°C, and S130G T 45°C), kinetic instability at higher temperature, and comparative dynamic instability correlate the fact that resistance to beta-lactam/beta-lactamase inhibitor combinations will likely not arise from the structural alteration of BlaC, therefore establishing confidence that this therapeutic modality can be potentially applied as a part of a successful treatment regimen against M...."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Two β-lactamase variants with reduced clavulanic acid inhibition display different millisecond dynamics. (PubMed, Antimicrob Agents Chemother) - "The crystal structure suggests multiple conformations for several side chains (e.g. Ser104, Ser130) and a short loop (214-216). In the K234R mutant, the active site dynamics are significantly diminished with respect to the wild type enzyme. These results show that multiple evolutionary routes are available to increase inhibitor resistance in BlaC and that active site dynamics on the millisecond time scale are not required for catalytic function."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Structural and biochemical characterization of the novel CTX-M-151 extended-spectrum β-lactamase and its inhibition by Avibactam. (PubMed, Antimicrob Agents Chemother) - "Upon acylation, the side chain of Lys73 points towards Ser130 which is associated with the protonation of Glu166, supporting the role of Lys73 in the proton-relay pathway and Glu166 as the general base in deacylation. To our knowledge, this is the first chromosomally-encoded CTX-M in Salmonella Choleraesuis that shows similar hydrolytic preference towards cefotaxime/ceftriaxone when compared to ceftazidime."

Journal

LC-MS Quantification of Site-Specific Phosphorylation Degree by Stable-Isotope Dimethyl Labeling Coupled with Phosphatase Dephosphorylation. (PubMed, Molecules) - "The phosphorylation degree of Ser130 on α-S1-casein was also validated by absolute quantification with the corresponding synthetic phosphorylated and nonphosphorylated peptides under a selected reaction monitoring (SRM) mode...The results showed that the absolute phosphorylation degree obtained from the (DM + deP) approach was comparable with the relative quantitation resulting from stable-isotope dimethyl labeling coupled with TiO enrichment. This study suggested that the (DM + deP) approach is promising for absolute quantification of site-specific degrees of phosphorylation in proteins, and it may provide more convincing information than the relative quantification method."

Journal • HSPB1

A Drug-Resistant β-lactamase Variant Changes the Conformation of Its Active Site Proton Shuttle to Alter Substrate Specificity and Inhibitor Potency. (PubMed, J Biol Chem) - "Located adjacent to proton shuttle residue Ser130, it is suggested to play a role in proton transfer during catalysis of the antibiotics. The mechanism underpinning how substitutions in this position modulate inhibitor efficiency and substrate specificity leading to drug resistance is unclear. The K234R substitution identified in several inhibitor-resistant β-lactamase variants is associated with decreased potency of the inhibitor clavulanic acid, which is used in combination with amoxicillin to overcome β-lactamase-mediated antibiotic resistance. Here we show that for CTX-M-14 β-lactamase, while Lys 234 is required for hydrolysis of cephalosporins such as cefotaxime, either lysine or arginine is sufficient for hydrolysis of ampicillin. Structural results suggest the slow acylation by the K234R enzyme is due to a conformational change in Ser130, and this change also leads to decreased inhibition potency of clavulanic acid. Because other inhibitor..."

Journal

In-silico virtual screening for identification of potent inhibitor for L2-β-lactamase from Stenotrophomonas maltophilia through molecular docking, molecular dynamics analysis study. (PubMed, J Biomol Struct Dyn) - "The ZINC35053014 compound had the highest binding energy: -8.51Kcal/mol with hydrophobic interaction at THR235 and formation of hydrogen bonds at SER70, SER130, ASN170, LYS234, THR235, SER237, and ARG244...These selected virtual hit compounds can be experimentally verified and used as lead compounds for the future search of β-Lactamase potent inhibitors for S. maltophilia. Communicated by Ramaswamy H. Sarma."

Journal • Infectious Disease

Probing the role of the conserved residue Glu166 in a class A β-lactamase using neutron and X-ray protein crystallography. (PubMed, Acta Crystallogr D Struct Biol) - "The amino-acid sequence of the Toho-1 β-lactamase contains several conserved residues in the active site, including Ser70, Lys73, Ser130 and Glu166, some of which coordinate a catalytic water molecule...This structure reveals that while the Glu166Gln mutation has a somewhat limited impact on the positions of the conserved amino acids within the active site, it displaces the catalytic water molecule from the active site. These subtle changes offer a structural explanation for the previously observed decreases in the binding of non-β-lactam inhibitors such as the recently developed diazobicyclooctane inhibitor avibactam."

Journal

Structural insights into the inhibition of the extended-spectrum β-lactamase PER-2 by Avibactam. (PubMed, Antimicrob Agents Chemother) - "The main biochemical and structural observations revealed the following: (i) both amino-acid substitutions in Arg220 and the rich hydrophobic content in the active site hinder the binding of catalytic waters and acylation, impairing AVI inhibition; (ii) movement of Ser130 upon binding of AVI favors the formation of a hydrogen bond with the sulfate group of AVI; and (iii) the Thr237Ala substitution alters the AVI inhibition constants. Comparatively, relebactam combined with a β-lactam is more potent against Escherichia coli producing PER-2 variants than β-lactam-AVI combinations. Our findings provide rationale for evaluating the utility of the currently available DBO inhibitors against unique ESBLs like PER-2 and anticipate the effectiveness of these inhibitors towards variants that may eventually be selected upon AVI usage."

Journal

Molecular Insights on the Release of Avibactam from the Acyl-Enzyme Complex. (PubMed, Biophys J) - "Our results show that unlike that observed in the acylation reaction, the residues Glu166 and Lys73 would be in their neutral forms. Release of avibactam follows a stepwise mechanism in which the first stage corresponds to the formation of a tetrahedral intermediate, whereas the second stage corresponds to the cleavage of the Ser70-C7 bond, mediated by Lys73, either directly or through Ser130."

Journal

Chronic mild stress-induced alterations of local protein synthesis: a role for cognitive impairment. (PubMed) - ACS Chem Neurosci - "Here, using the chronic mild stress (CMS) paradigm of depression, we found that, independently from the anhedonic phenotype, CMS rats showed a deficit in the novel object recognition (NOR) test, which is associated with an inability to phosphorylate GluN2B subunit on Ser1303 and to activate the mTOR pathway. Interestingly, we found a significant increase of oligophrenin-1 (2 uORFs) and of Bmal1 (7 uORFs) protein levels specifically in the control animals exposed to the NOR test. Our results demonstrated that the cognitive decline associated with stress exposure might be due to alterations in local protein translation of specific mRNAs, suggesting that a pharmacological intervention able to correct these defects might be useful in the improvement of deteriorated functions in patients with major depression and stress-related disorders."

Journal • Alzheimer's Disease • Biosimilar • CNS Disorders • Depression

CaMKII-mediated phosphorylation of GluN2B regulates recombinant NMDA receptor currents in a chloride-dependent manner. (PubMed, Mol Cell Neurosci) - "In support of this idea, CaMKIIα modulation of GluN2B-NMDA receptors is abrogated by the phospho-null mutation of Ser1303 in GluN2B to alanine and occluded by phospho-mimetic mutation of Ser1303 to aspartate regardless of intracellular Cl(-) concentration. Thus, CaMKII-mediated phosphorylation of GluN2B-containing NMDA receptors reduces desensitization at physiological (low) intracellular Cl(-), perhaps serving as a feed-forward mechanism to sustain NMDA-mediated Ca(2+) entry and continued CaMKII activation during learning and memory."

Journal • Biosimilar

Structural insights into the TLA-3 extended-spectrum β-lactamase and its inhibition by avibactam and OP0595. (PubMed, Antimicrob Agents Chemother) - "...Avibactam and OP0595 bound covalently to TLA-3 via the Ser70 residue, and made contacts with residues Ser130, Thr235, and Ser237, which are conserved in ESBLs. Additionally, the sulfate group of the inhibitors formed polar contacts with amino acid residues in a positively charged pocket of TLA-3. Our findings provide a structural template for designing improved diazabicyclooctane-based inhibitors that are effective against ESBL-producing Enterobacteriaceae."

Journal • Biosimilar

SCF-mediated degradation of TOP2β promotes cancer cell survival in response to chemotherapeutic drugs targeting topoisomerase II. (PubMed, Oncogenesis) - "Specifically, DNA damage signal, triggered by teniposide (VM-26) treatment, activates ATM, cooperating with CK1 to phosphorylate TOP2β on Ser1134 and Ser1130, respectively, in a canonical degron motif to facilitate β-TrCP binding and subsequent degradation...Thus, it appears that TOP2β degradation is a cellular defensive mechanism to facilitate the exposure of DSBs to trigger DNA damage response and repair. Collectively, our findings reveal a new strategy to improve the efficacy of TOP2 poisons in combination with small-molecule inhibitors against TOP2β degradation."

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CK2-mediated CCDC106 phosphorylation is required for p53 degradation in cancer progression. (PubMed, J Exp Clin Cancer Res) - "This study revealed a CK2/CCDC106/p53 signaling axis in the progression of breast and cervical cancers, which may provide a new therapeutic target for cancer treatment."

Journal

Phosphorylated Progesterone Receptor Isoforms Mediate Opposing Stem-Like and Proliferative Breast Cancer Cell Fates (ENDO 2019) - "...In contrast to previous reports, we report robust phosphorylation of PR-A relative to PR-B Ser294 (i.e. Ser130 in PR-A) and show that this residue is required for PR-A-induced expression of CSC-associated genes and CSC behavior in vitro...The FOXO1 inhibitor (AS1842856) alone or in combination with onapristone (PR antagonist) blunted phospho-PR (Ser294) and tumorsphere formation in PR-A+ and PR-B+ T47D cells and unmodified ER+/PR+ MCF-7 and BT474 breast cancer models...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*"