Biology subjects

Yeasmin, M.

Publications and source records attributed to Yeasmin, M..

4 recordsLinked to original sources

bioRxiv2026

Structural basis of MK-97 positive allosteric modulation at the M4 mAChR

Positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor (mAChR) represent a promising therapeutic strategy for treating cognitive deficits and neuropsychiatric disorders. While first-generation M4 mAChR PAMs, like LY2033298, demonstrated proof-of-concept, second-generation compounds, such as MK-97, exhibit substantially improved potency and reduced species variability. Here we report the cryo-EM structure of the M4 mAChR bound to the endogenous agonist, acetylcholine, and MK-97 at 2.7 [A] resolution, revealing the molecular basis for improved M4 mAChR PAM activity. MK-97 adopts a distinctive boomerang-shaped conformation within the extracellular-facing allosteric binding site, with a central pyridine vertex, a lower cyclopentylmethylpyrazole arm extending toward the floor of the orthosteric site, and an upper isoindolinone arm projecting toward extracellular loop 2 (ECL2). This extended binding mode establishes a distributed interaction network across transmembrane helices TM2, TM3, TM5, TM6, and TM7, with key contacts including a hydrogen bond with Y922.64 and a {pi}-{pi} stacking interaction with W4357.35. Integration of structural data, molecular dynamics simulations, and mutagenesis validation reveals that the high affinity of MK-97 derives from optimized engagement across all three binding regions rather than dependence on any single critical contact. Insights from comprehensive structure-activity relationship (SAR) studies provide a molecular framework for the rational design of next-generation M4 mAChR PAMs with improved pharmacological properties. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=70 SRC="FIGDIR/small/723386v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@75cb90org.highwire.dtl.DTLVardef@1876c9corg.highwire.dtl.DTLVardef@1eba8d0org.highwire.dtl.DTLVardef@9818ad_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

Metatranscriptomic Insights into Host-Microbiome Interactions Underlying Asymptomatic COVID-19 Cases

In recent years, the research on Coronavirus disease 2019 (COVID-19) has surged rapidly due to its infectious nature and epidemiological importance as a pandemic. Association of other pathogenic microbes or different human microbiomes with COVID-19 severity is well established. While much is known about COVID-19, studies exploring how host-pathogen interactions at the transcriptomic level influence disease severity are still limited. This research focuses on metatranscriptomic perspective of COVID-19 patients from different Bangladeshi cohorts. Metatranscriptomic sequencing was performed using the extracted RNA of forty different nasopharyngeal samples. After preprocessing and assembly of the genome sequence data, taxonomic identification and diversity along with antibiotic resistance pattern was analyzed using different bioinformatic pipelines. COVID-19 positive and asymptomatic positive patients had a higher abundance of pathogenic and multidrug resistant bacteria whereas the Healthy or recovered patients had higher fungal population. Differential gene expression analysis was also performed to identify the upregulated and downregulated genes responsible for different biological and immunological pathways of humans. Here, immunological response related genes were mostly upregulated in positive cases which was also evident in the proinflammatory cytokines upregulation. Moreover, asymptomatic positive cases showed low TLR-4 expression, which is key to recognizing pathogen-associated molecular patterns (PAMPs) and triggering pro-inflammatory immune responses. This study can clarify the gene expression and signaling pattern of COVID-19 patients with different severity. This may also suggest that some populations exhibit reduced basal expression of TLR-4, which may suppress innate immune activation following infection and contribute to asymptomatic clinical outcomes; however, this hypothesis requires further investigation. Future studies should aim to validate these associations using larger, ethnically diverse cohorts with comprehensive clinical and demographic data.

microbiology↗

bioRxiv2025

Cryo-EM reveals a new allosteric binding site at the M5 mAChR

The M5 muscarinic acetylcholine receptor (M5 mAChR) represents a promising therapeutic target for neurological disorders. However, the high conservation of its orthosteric binding site has posed significant challenges for drug development. While selective positive allosteric modulators (PAMs) offer a potential solution, a structural understanding of the M5 mAChR and its allosteric binding sites has remained limited. Here, we present a 2.8 [A] cryo-electron microscopy structure of the M5 mAChR complexed with heterotrimeric Gq protein and the agonist iperoxo, completing the active-state structural characterization of the mAChR family. To identify the binding site of M5-selective PAMs, we implemented an integrated approach combining mutagenesis, pharmacological assays, structural biology, and molecular dynamics simulations. Our mutagenesis studies revealed that selective M5 PAMs bind outside previously characterized M5 mAChR allosteric sites. Subsequently, we obtained a 2.1 [A] structure of M5 mAChR co-bound with acetylcholine and the selective PAM VU6007678, revealing a novel allosteric pocket at the extrahelical interface between transmembrane domains 3 and 4 that was confirmed through mutagenesis and simulations. These findings demonstrate the diverse mechanisms of allosteric regulation in mAChRs and highlight the value of integrating pharmacological and structural approaches to identify novel allosteric binding sites.

pharmacology and toxicology↗

bioRxiv2022

Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics

Allosteric modulation of G protein-coupled receptors (GPCRs) is a major paradigm in drug discovery. Despite decades of research, a molecular level understanding of the general principals that govern the myriad pharmacological effects exerted by GPCR allosteric modulators remains limited. The M4 muscarinic acetylcholine receptor (M4 mAChR) is a well-validated and clinically relevant allosteric drug target for several major psychiatric and cognitive disorders. Here, we present high-resolution cryo-electron microscopy structures of the M4 mAChR bound to a cognate Gi1 protein and the high affinity agonist, iperoxo, in the absence and presence of two different positive allosteric modulators, LY2033298 or VU0467154. We have also determined the structure of the M4 mAChR-Gi1 complex bound to its endogenous agonist, acetylcholine (ACh). Structural comparisons, together with molecular dynamics, mutagenesis, and pharmacological validations, have provided in-depth insights into the role of structure and dynamics in orthosteric and allosteric ligand binding, global mechanisms of receptor activation, cooperativity, probe-dependence, and species variability; all key hallmarks underpinning contemporary GPCR drug discovery.

pharmacology and toxicology↗