6U3X

PCSK9 in complex with compound 2

Summary for 6U3X

• Entry DOI: 10.2210/pdb6u3x/pdb
• Descriptor: Proprotein convertase subtilisin/kexin type 9, 2-[(1R)-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl]-N-(1,3-thiazol-2-yl)acetamide (3 entities in total)
• Functional Keywords: serine type endopeptidase activity proteolysis, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 152510.74

Authors

Lu, J.,Soisson, S. (deposition date: 2019-08-22, release date: 2019-11-06, Last modification date: 2024-10-30)

Primary citation

Petrilli, W.L.,Adam, G.C.,Erdmann, R.S.,Abeywickrema, P.,Agnani, V.,Ai, X.,Baysarowich, J.,Byrne, N.,Caldwell, J.P.,Chang, W.,DiNunzio, E.,Feng, Z.,Ford, R.,Ha, S.,Huang, Y.,Hubbard, B.,Johnston, J.M.,Kavana, M.,Lisnock, J.M.,Liang, R.,Lu, J.,Lu, Z.,Meng, J.,Orth, P.,Palyha, O.,Parthasarathy, G.,Salowe, S.P.,Sharma, S.,Shipman, J.,Soisson, S.M.,Strack, A.M.,Youm, H.,Zhao, K.,Zink, D.L.,Zokian, H.,Addona, G.H.,Akinsanya, K.,Tata, J.R.,Xiong, Y.,Imbriglio, J.E.
From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9.
Cell Chem Biol, 27:32-40.e3, 2020

PubMed Abstract: Proprotein convertase substilisin-like/kexin type 9 (PCSK9) is a serine protease involved in a protein-protein interaction with the low-density lipoprotein (LDL) receptor that has both human genetic and clinical validation. Blocking this protein-protein interaction prevents LDL receptor degradation and thereby decreases LDL cholesterol levels. Our pursuit of small-molecule direct binders for this difficult to drug PPI target utilized affinity selection/mass spectrometry, which identified one confirmed hit compound. An X-ray crystal structure revealed that this compound was binding in an unprecedented allosteric pocket located between the catalytic and C-terminal domain. Optimization of this initial hit, using two distinct strategies, led to compounds with high binding affinity to PCSK9. Direct target engagement was demonstrated in the cell lysate with a cellular thermal shift assay. Finally, ligand-induced protein degradation was shown with a proteasome recruiting tag attached to the high-affinity allosteric ligand for PCSK9.

PubMed: 31653597
DOI: 10.1016/j.chembiol.2019.10.002

Experimental method

X-RAY DIFFRACTION (2.64 Å)