7kfa

PCSK9 in complex with PCSK9i a 13mer cyclic peptide LDLR disruptor

spinqualitylabelsall models 7kfa, resolution 2.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7kfa 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 2.45Å Ligands: ACE, CA, NEH, WCM 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/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting hepatic LDL receptor (LDLR) degradation. Therapeutic antibodies that disrupt PCSK9-LDLR binding reduce LDL-C concentrations and cardiovascular disease risk. The epidermal growth factor precursor homology domain A (EGF-A) of the LDLR serves as a primary contact with PCSK9 via a flat interface, presenting a challenge for identifying small molecule PCSK9-LDLR disruptors. We employ an affinity-based screen of 10(13)in vitro-translated macrocyclic peptides to identify high-affinity PCSK9 ligands that utilize a unique, induced-fit pocket and partially disrupt the PCSK9-LDLR interaction. Structure-based design led to molecules with enhanced function and pharmacokinetic properties (e.g., (13)PCSK9i). In mice, (13)PCSK9i reduces plasma cholesterol levels and increases hepatic LDLR density in a dose-dependent manner. (13)PCSK9i functions by a unique, allosteric mechanism and is the smallest molecule identified to date with in vivo PCSK9-LDLR disruptor function. Identification of a PCSK9-LDLR disruptor peptide with in vivo function.,Brousseau ME, Clairmont KB, Spraggon G, Flyer AN, Golosov AA, Grosche P, Amin J, Andre J, Burdick D, Caplan S, Chen G, Chopra R, Ames L, Dubiel D, Fan L, Gattlen R, Kelly-Sullivan D, Koch AW, Lewis I, Li J, Liu E, Lubicka D, Marzinzik A, Nakajima K, Nettleton D, Ottl J, Pan M, Patel T, Perry L, Pickett S, Poirier J, Reid PC, Pelle X, Seepersaud M, Subramanian V, Vera V, Xu M, Yang L, Yang Q, Yu J, Zhu G, Monovich LG Cell Chem Biol. 2022 Feb 17;29(2):249-258.e5. doi: , 10.1016/j.chembiol.2021.08.012. Epub 2021 Sep 20. PMID:34547225 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also PCSK9

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