7TA6

Trimer-to-Monomer Disruption of Tumor Necrosis Factor-alpha (TNF-alpha) by unnatural alpha/beta-peptide-1

Summary for 7TA6

• Entry DOI: 10.2210/pdb7ta6/pdb
• Descriptor: Tumor necrosis factor, Alpha/Beta-peptide-1, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: tumor necrosis factor-alpha, signaling, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 16
• Total formula weight: 166676.45

Authors

Niu, J.,Bingman, C.A.,Gellman, S.H. (deposition date: 2021-12-20, release date: 2022-06-29, Last modification date: 2024-04-03)

Primary citation

Niu, J.,Cederstrand, A.J.,Eddinger, G.A.,Yin, B.,Checco, J.W.,Bingman, C.A.,Outlaw, V.K.,Gellman, S.H.
Trimer-to-Monomer Disruption Mechanism for a Potent, Protease-Resistant Antagonist of Tumor Necrosis Factor-alpha Signaling.
J.Am.Chem.Soc., 144:9610-9617, 2022

PubMed Abstract: Aberrant tumor necrosis factor-α (TNFα) signaling is associated with many inflammatory diseases. The homotrimeric quaternary structure of TNFα is essential for receptor recognition and signal transduction. Previously, we described an engineered α/β-peptide inhibitor that potently suppresses TNFα activity and resists proteolysis. Here, we present structural evidence that both the α/β-peptide inhibitor and an all-α analogue bind to a monomeric form of TNFα. Calorimetry data support a 1:1 inhibitor/TNFα stoichiometry in solution. In contrast, previous cocrystal structures involving peptide or small-molecule inhibitors have shown the antagonists engaging a TNFα dimer. The structural data reveal why our inhibitors favor monomeric TNFα. Previous efforts to block TNFα-induced cell death with peptide inhibitors revealed that surfactant additives to the assay conditions cause a more rapid manifestation of inhibitory activity than is observed in the absence of additives. We attributed this effect to a loose surfactant TNFα association that lowers the barrier to trimer dissociation. Here, we used the new structural data to design peptide inhibitors bearing a surfactant-inspired appendage intended to facilitate TNFα trimer dissociation. The appendage modified the time course of protection from cell death.

PubMed: 35613436
DOI: 10.1021/jacs.1c13717

Experimental method

X-RAY DIFFRACTION (2.67 Å)