7L9X

Structure of VPS4B in complex with an allele-specific covalent inhibitor

Summary for 7L9X

• Entry DOI: 10.2210/pdb7l9x/pdb
• Descriptor: Vacuolar protein sorting-associated protein 4B, N-{3-[(8-phenyl[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino]phenyl}propanamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: chemical inhibitor, hydrolase, atpase, aaa superfamily, protein transport
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 50039.73

Authors

Grasso, M.,Cupido, T.,Kapoor, T.M. (deposition date: 2021-01-05, release date: 2021-04-14, Last modification date: 2024-10-30)

Primary citation

Cupido, T.,Jones, N.H.,Grasso, M.J.,Pisa, R.,Kapoor, T.M.
A chemical genetics approach to examine the functions of AAA proteins.
Nat.Struct.Mol.Biol., 28:388-397, 2021

PubMed Abstract: The structural conservation across the AAA (ATPases associated with diverse cellular activities) protein family makes designing selective chemical inhibitors challenging. Here, we identify a triazolopyridine-based fragment that binds the AAA domain of human katanin, a microtubule-severing protein. We have developed a model for compound binding and designed ASPIR-1 (allele-specific, proximity-induced reactivity-based inhibitor-1), a cell-permeable compound that selectively inhibits katanin with an engineered cysteine mutation. Only in cells expressing mutant katanin does ASPIR-1 treatment increase the accumulation of CAMSAP2 at microtubule minus ends, confirming specific on-target cellular activity. Importantly, ASPIR-1 also selectively inhibits engineered cysteine mutants of human VPS4B and FIGL1-AAA proteins, involved in organelle dynamics and genome stability, respectively. Structural studies confirm our model for compound binding at the AAA ATPase site and the proximity-induced reactivity-based inhibition. Together, our findings suggest a chemical genetics approach to decipher AAA protein functions across essential cellular processes and to test hypotheses for developing therapeutics.

PubMed: 33782614
DOI: 10.1038/s41594-021-00575-9

Experimental method

X-RAY DIFFRACTION (2.81 Å)