9YSH

Allosteric inhibitor of human DNA polymerase theta

This is a non-PDB format compatible entry.

Summary for 9YSH

• Entry DOI: 10.2210/pdb9ysh/pdb
• Descriptor: DNA polymerase theta, DNA (5'-D(*CP*GP*TP*CP*CP*AP*AP*TP*GP*AP*CP*AP*GP*CP*C)-3'), DNA (5'-D(*GP*GP*CP*TP*GP*TP*CP*AP*TP*TP*G)-3'), ... (8 entities in total)
• Functional Keywords: inhibitor, complex, dna binding protein, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 171577.60

Authors

Mader, P.,Sicheri, F. (deposition date: 2025-10-18, release date: 2026-05-20)

Primary citation

Bubenik, M.,Mader, P.,Orlicky, S.,Perryman, A.L.,Hamel, M.,Godbout, C.,Falgueyret, J.P.,Kurinov, I.,Wong, C.,Gingras, A.C.,Mamane, Y.,Zinda, M.,Morris, S.J.,Gallant, M.,Sfeir, A.,Black, W.C.,Durocher, D.,Zimmermann, M.,Sicheri, F.
Design of a Targeted Covalent Probe to Interrogate the DNA Polymerase Activity of Pol theta.
Acs Med.Chem.Lett., 17:433-440, 2026

PubMed Abstract: Human DNA polymerase θ (Polθ) is essential for microhomology-mediated end-joining (MMEJ) and represents a therapeutic vulnerability in homologous recombination (HR)-deficient cancers. Although reversible inhibitors of Polθ have advanced into clinical development, covalent chemical probes remain unexplored. Analysis of a previously described structure of the reversible inhibitor bound to Polθ identified Cys2411 as an accessible residue 7.4 Å adjacent to the inhibitor binding site. Guided by X-ray crystallographic studies, we designed to reduce the separating distance between inhibitor and Cys2411 to 4.7 Å and then synthesized by incorporating a vinyl sulfone electrophile. Functional studies revealed efficient covalent linkage to Cys2411 ( = 11.6 s), while a high-resolution (2.0 Å) cocrystal structure validated the design strategy. These findings establish Cys2411 as a privileged site for covalent inhibitor development and provide a highly potent, selective chemical probe useful for investigating Polθ biology.

PubMed: 41704370
DOI: 10.1021/acsmedchemlett.5c00643

Experimental method

X-RAY DIFFRACTION (2.71 Å)