6X27

Lon protease proteolytic domain complexed with bortezomib

Summary for 6X27

• Entry DOI: 10.2210/pdb6x27/pdb
• Related: 6WYS 6WZV 6X1M
• Descriptor: Lon protease homolog, mitochondrial, N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL)-L-PHENYLALANINAMIDE, PENTAETHYLENE GLYCOL, ... (5 entities in total)
• Functional Keywords: covalent inhibitor, proteolytic domain, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 12
• Total formula weight: 291683.35

Authors

Lee, C.C.,Spraggon, G. (deposition date: 2020-05-20, release date: 2021-04-14, Last modification date: 2024-10-23)

Primary citation

Kingsley, L.J.,He, X.,McNeill, M.,Nelson, J.,Nikulin, V.,Ma, Z.,Lu, W.,Zhou, V.W.,Manuia, M.,Kreusch, A.,Gao, M.Y.,Witmer, D.,Vaillancourt, M.T.,Lu, M.,Greenblatt, S.,Lee, C.,Vashisht, A.,Bender, S.,Spraggon, G.,Michellys, P.Y.,Jia, Y.,Haling, J.R.,Lelais, G.
Structure-Based Design of Selective LONP1 Inhibitors for Probing In Vitro Biology.
J.Med.Chem., 64:4857-4869, 2021

PubMed Abstract: LONP1 is an AAA+ protease that maintains mitochondrial homeostasis by removing damaged or misfolded proteins. Elevated activity and expression of LONP1 promotes cancer cell proliferation and resistance to apoptosis-inducing reagents. Despite the importance of LONP1 in human biology and disease, very few LONP1 inhibitors have been described in the literature. Herein, we report the development of selective boronic acid-based LONP1 inhibitors using structure-based drug design as well as the first structures of human LONP1 bound to various inhibitors. Our efforts led to several nanomolar LONP1 inhibitors with little to no activity against the 20S proteasome that serve as tool compounds to investigate LONP1 biology.

PubMed: 33821636
DOI: 10.1021/acs.jmedchem.0c02152

Experimental method

X-RAY DIFFRACTION (2.12 Å)