6X1Y

Mre11 dimer in complex with small molecule modulator PFMI

Summary for 6X1Y

• Entry DOI: 10.2210/pdb6x1y/pdb
• Descriptor: Nuclease SbcCD subunit D, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, (5Z)-5-[(3-methoxyphenyl)methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one, ... (4 entities in total)
• Functional Keywords: dna repair mre11 thermophilic nuclease, dna double-strand break repair, hydrolase
• Biological source: Thermotoga maritima
• Total number of polymer chains: 2
• Total formula weight: 78043.55

Authors

Arvai, A.S.,Moiani, D.,Tainer, J.A. (deposition date: 2020-05-19, release date: 2020-06-10, Last modification date: 2023-10-18)

Primary citation

Wilson 3rd, D.M.,Deacon, A.M.,Duncton, M.A.J.,Pellicena, P.,Georgiadis, M.M.,Yeh, A.P.,Arvai, A.S.,Moiani, D.,Tainer, J.A.,Das, D.
Fragment- and structure-based drug discovery for developing therapeutic agents targeting the DNA Damage Response.
Prog.Biophys.Mol.Biol., 163:130-142, 2021

PubMed Abstract: Cancer will directly affect the lives of over one-third of the population. The DNA Damage Response (DDR) is an intricate system involving damage recognition, cell cycle regulation, DNA repair, and ultimately cell fate determination, playing a central role in cancer etiology and therapy. Two primary therapeutic approaches involving DDR targeting include: combinatorial treatments employing anticancer genotoxic agents; and synthetic lethality, exploiting a sporadic DDR defect as a mechanism for cancer-specific therapy. Whereas, many DDR proteins have proven "undruggable", Fragment- and Structure-Based Drug Discovery (FBDD, SBDD) have advanced therapeutic agent identification and development. FBDD has led to 4 (with ∼50 more drugs under preclinical and clinical development), while SBDD is estimated to have contributed to the development of >200, FDA-approved medicines. Protein X-ray crystallography-based fragment library screening, especially for elusive or "undruggable" targets, allows for simultaneous generation of hits plus details of protein-ligand interactions and binding sites (orthosteric or allosteric) that inform chemical tractability, downstream biology, and intellectual property. Using a novel high-throughput crystallography-based fragment library screening platform, we screened five diverse proteins, yielding hit rates of ∼2-8% and crystal structures from ∼1.8 to 3.2 Å. We consider current FBDD/SBDD methods and some exemplary results of efforts to design inhibitors against the DDR nucleases meiotic recombination 11 (MRE11, a.k.a., MRE11A), apurinic/apyrimidinic endonuclease 1 (APE1, a.k.a., APEX1), and flap endonuclease 1 (FEN1).

PubMed: 33115610
DOI: 10.1016/j.pbiomolbio.2020.10.005

Experimental method

X-RAY DIFFRACTION (2.35 Å)