human low density lipoprotein receptor  (Cusabio)

Journal: bioRxiv

Article Title: Programming Biomolecular Interactions with All-Atom Generative Model

doi: 10.64898/2026.03.12.711044

Figure Lengend Snippet: First, orthosteric peptides were designed against PCSK9. Furthermore, identification of an allosteric binding site enabled the design of small-molecule inhibitors with a potentially novel mechanism of action (MoA). a , Schematic representation of physiological LDLR recycling and LDL clearance. LDL binds LDLR at the cell surface, is internalized via endocytosis, and subsequently degraded in lysosomes, while LDLR is recycled back to the cell surface. b , Schematic representation of PCSK9-mediated lysosomal degradation of LDLR. PCSK9 binding promotes internalization and degradation of the PCSK9–LDLR complex, reducing LDLR abundance and increasing circulating LDL. c , Schematic representation orthosteric and allosteric inhibition of PCSK9 function. Orthosteric inhibitors directly block the PCSK9–LDLR interaction, whereas the identified allosteric inhibitors are likely to hinder PCSK9 secretion, thereby indirectly preventing PCSK9-mediated LDLR degradation. d , Left: Orthosteric and allosteric binding sites on PCSK9, with the allosteric site revealed by AlphaFold3 prediction of the complex between PCSK9 and a clinical-stage compound lacking structural or mechanistic characterization . Right: Distribution of measured K d levels for designed orthosteric peptides and allosteric small molecules. e-f , Designed structures of PCSK9-peptide-7 and PCSK9-peptide-3, as well as their binding affinity to PCSK9 determined by SPR. g-h , Designed structures of PCSK9-compound-3 and PCSK9-compound-6, as well as their binding affinity to PCSK9 determined by SPR. Crystal structure is solved for PCSK9-compound-3, and exhibits an RMSD of 0.92 Å to the designed structure. i , Cell-based assays showing concentration-dependent upregulation of LDLR and inhibition of PCSK9 secretion, with AZD0780 (from TOPSCIENCE, TSID: T64362, CAS: 2455427-91-3) as the positive control. Both assays were measured with triplicates (N=3), and the error bars represent the standard deviations. Panel a-c were created using BioRender ( https://biorender.com ).

Article Snippet: LDLR levels were quantified using a human LDLR ELISA kit (R&D Systems, DLDLR0) according to the manufacturer’s instructions.

Techniques: Binding Assay, Inhibition, Blocking Assay, Concentration Assay, Positive Control

Journal: Journal of Enzyme Inhibition and Medicinal Chemistry

Article Title: Identification of a peptide inhibitor disrupting the PCSK9-LDLR interaction via pharmacophore-based virtual screening, molecular dynamics simulations and in vitro/vivo evaluation

doi: 10.1080/14756366.2025.2610849

Figure Lengend Snippet: The pharmacophore model of the LDLR-binding domain in PCSK9 was established using MOE. Pharmacophore features include: F1, an aromatic feature; F2 and F4, hydrogen-bond acceptor features; F3, a hydrogen-bond donor feature.

Article Snippet: The supernatants were used to determine hepatic LDLR protein levels using a mouse LDLR ELISA kit (R&D Systems).

Techniques: Binding Assay

Journal: Journal of Enzyme Inhibition and Medicinal Chemistry

Article Title: Identification of a peptide inhibitor disrupting the PCSK9-LDLR interaction via pharmacophore-based virtual screening, molecular dynamics simulations and in vitro/vivo evaluation

doi: 10.1080/14756366.2025.2610849

Figure Lengend Snippet: The 2D interaction plots for TPPs 1–5 and the LDLR-binding domain in PCSK9 using the LigPlot. The hydrogen bonds are shown in green.

Article Snippet: The supernatants were used to determine hepatic LDLR protein levels using a mouse LDLR ELISA kit (R&D Systems).

Techniques: Binding Assay

Journal: Journal of Enzyme Inhibition and Medicinal Chemistry

Article Title: Identification of a peptide inhibitor disrupting the PCSK9-LDLR interaction via pharmacophore-based virtual screening, molecular dynamics simulations and in vitro/vivo evaluation

doi: 10.1080/14756366.2025.2610849

Figure Lengend Snippet: The 3D interaction plots for TPPs 1–5 and the LDLR-binding domain in PCSK9. (A, B) TPP-1 are colour-coded by yellow. (C, D) TPP-2, purple; (E, F) TPP-3, orange; (G, H) TPP-4, cyan; (I, J) TPP-5, green. The LDLR-binding domain residues of PCSK9 are displayed as sticks: nitrogen atoms are blue, oxygen atoms are red, and other residues are silver.

Article Snippet: The supernatants were used to determine hepatic LDLR protein levels using a mouse LDLR ELISA kit (R&D Systems).

Techniques: Binding Assay

Journal: Journal of Enzyme Inhibition and Medicinal Chemistry

Article Title: Identification of a peptide inhibitor disrupting the PCSK9-LDLR interaction via pharmacophore-based virtual screening, molecular dynamics simulations and in vitro/vivo evaluation

doi: 10.1080/14756366.2025.2610849

Figure Lengend Snippet: The surface LDLR expression in HepG2 cells. (A) HepG2 cells treated with TPPs 1–5, Pep2-8, and Evolocumab. (B) HepG2 cells treated with TPP-4 at different concentrations. *** P < 0.001 vs Pep2-8.

Article Snippet: The supernatants were used to determine hepatic LDLR protein levels using a mouse LDLR ELISA kit (R&D Systems).

Techniques: Expressing

Journal: Journal of Enzyme Inhibition and Medicinal Chemistry

Article Title: Identification of a peptide inhibitor disrupting the PCSK9-LDLR interaction via pharmacophore-based virtual screening, molecular dynamics simulations and in vitro/vivo evaluation

doi: 10.1080/14756366.2025.2610849

Figure Lengend Snippet: (A) Liver LDLR levels in mice treated with TPP-4 and Evolocumab. (B) Plasma total cholesterol levels in mice treated with TPP-4 and Evolocumab.

Article Snippet: The supernatants were used to determine hepatic LDLR protein levels using a mouse LDLR ELISA kit (R&D Systems).

Techniques: Clinical Proteomics