7s5g

PCSK9 in complex with compound 19

spinqualitylabelsall models 7s5g, resolution 2.04Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7s5g 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 2.041Å Ligands: 0A1, 3WX, 89N, B74, DAL, DHL, FTR, GOL, MPT 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 Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. Starting from second-generation lead structures such as 2, we were able to refine these structures to obtain extremely potent bi- and tricyclic PCSK9 inhibitor peptides. Optimized molecules such as 44 demonstrated sufficient oral bioavailability to maintain therapeutic levels in rats and cynomolgus monkeys after dosing with an enabled formulation. We demonstrated target engagement and LDL lowering in cynomolgus monkeys essentially identical to those observed with the clinically approved, parenterally dosed antibodies. These molecules represent the first report of highly potent and orally bioavailable macrocyclic peptide PCSK9 inhibitors with overall profiles favorable for potential development as once-daily oral lipid-lowering agents. In this manuscript, we detail the design criteria and multiparameter optimization of this novel series of PCSK9 inhibitors. A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors.,Tucker TJ, Embrey MW, Alleyne C, Amin RP, Bass A, Bhatt B, Bianchi E, Branca D, Bueters T, Buist N, Ha SN, Hafey M, He H, Higgins J, Johns DG, Kerekes AD, Koeplinger KA, Kuethe JT, Li N, Murphy B, Orth P, Salowe S, Shahripour A, Tracy R, Wang W, Wu C, Xiong Y, Zokian HJ, Wood HB, Walji A J Med Chem. 2021 Nov 25;64(22):16770-16800. doi: 10.1021/acs.jmedchem.1c01599. , Epub 2021 Oct 27. PMID:34704436 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also PCSK9

Proteopedia Page Contributors and Editors (what is this?)

OCA