10sb | pdb_000010sb

PCSK9 in complex with cyclic peptide 21

spinqualitylabelsall models 10sb, resolution 1.83Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 10sb is a 3 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.828Å Ligands: 0A1, 2RA, 3WX, A1C8P, A1CHA, FTR, GOA, GOL, SIN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease PCSK9_HUMAN Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:603776. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins. Function PCSK9_HUMAN Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways. Publication Abstract from PubMed Herein, we report the discovery process of enlicitide (MK-0616, compound 18), an orally active macrocyclic peptide therapeutic against PCSK9 for LDL-C reduction. To overcome development bottlenecks in a prior lead (compound 1a) in a timely manner (sulfur oxidation liability, low solubility, azido potential manufacturing hazard, and alkene isomeric complexity), we deployed a novel scalable solution-phase modular fragment assembly (North/East/South/West/tail), which allowed us to accelerate the design-make-test-analyze (DMTA) cycle and preclinical profiling. Design solutions were quickly validated through this approach (a northern lactam staple, an N-benzylamide southern spacer, an RCM-derived cross-link in conjunction with solvent-exposed motifs to modulate solubility) and delivered compounds with low picomolar potency, improved solubility, stability, and PK from which enlicitide (MK-0616, compound 18) was selected for clinical progression. This modular strategy may act as a template to accelerate late-stage issue-driven SAR in highly engineered macrocyclic peptides. Discovery Process of Enlicitide, a Highly Engineered Macrocyclic Peptide Therapeutic, through Issue-Driven Fragment-Based Synthetic Assembly and SAR.,Josien H, Nair AG, Ding FX, Guo Y, Chen YH, Rao AU, Liu J, Tong L, Sun Z, Lo MM, Tucker TJ, Embrey MW, Shahripour A, Wu C, Bianchi E, Branca D, Kuethe JT, Lee J, Thaisrivongs DA, Bulger PG, Zhu X, Ha SN, Johnston JM, Klein DJ, Orth P, Hong MR, Buevich AV, Gao Q, Zokian HJ, Koeplinger KA, Tracy RW, Hafey MJ, Buist N, Bueters T, Alleyne C, Bass A, Campeau LC, Johns DG, Garbaccio RM, Vachal P, Walji A, Wood HB J Med Chem. 2026 May 27. doi: 10.1021/acs.jmedchem.6c00463. PMID:42201324 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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