8GH7

142D6 bound to BIR3-XIAP

Summary for 8GH7

• Entry DOI: 10.2210/pdb8gh7/pdb
• Related PRD ID: PRD_002528
• Descriptor: E3 ubiquitin-protein ligase XIAP, BIR3 inhibitor MAA-CHG-PRO-ZHW, ZINC ION, ... (5 entities in total)
• Functional Keywords: bir domain, protein-ligand complex, bir3 inhibitor, zinc finger motif, signaling protein, signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 24596.31

Authors

Garza-Granados, A.,McGuire, J.,Baggio, C.,Pellecchia, M.,Pegan, S.D. (deposition date: 2023-03-09, release date: 2023-07-05, Last modification date: 2023-07-12)

Primary citation

Udompholkul, P.,Garza-Granados, A.,Alboreggia, G.,Baggio, C.,McGuire, J.,Pegan, S.D.,Pellecchia, M.
Characterization of a Potent and Orally Bioavailable Lys-Covalent Inhibitor of Apoptosis Protein (IAP) Antagonist.
J.Med.Chem., 66:8159-8169, 2023

PubMed Abstract: We have recently reported on the use of aryl-fluorosulfates in designing water- and plasma-stable agents that covalently target Lys, Tyr, or His residues in the BIR3 domain of the inhibitor of the apoptosis protein (IAP) family. Here, we report further structural, cellular, and pharmacological characterizations of this agent, including the high-resolution structure of the complex between the Lys-covalent agent and its target, the BIR3 domain of X-linked IAP (XIAP). We also compared the cellular efficacy of the agent in two-dimensional (2D) and three-dimensional (3D) cell cultures, side by side with the clinical candidate reversible IAP inhibitor LCL161. Finally, pharmacokinetic studies indicated that the agent was long-lived and orally bioavailable. Collectively our data further corroborate that aryl-fluorosulfates, when incorporated correctly in a ligand, can result in Lys-covalent agents with pharmacodynamic and pharmacokinetic properties that warrant their use in the design of pharmacological probes or even therapeutics.

PubMed: 37262387
DOI: 10.1021/acs.jmedchem.3c00467

Experimental method

X-RAY DIFFRACTION (1.75 Å)