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8TQS

Complex of human thrombin (S195A) bound to a bivalent inhibitor comprised of DNA Aptamer HD22 conjugated to Dabigatran with a linker.

Summary for 8TQS
Entry DOI10.2210/pdb8tqs/pdb
DescriptorDNA (30-MER), Thrombin heavy chain, Prothrombin, ... (9 entities in total)
Functional Keywordshuman thrombin, dna aptamer, dabigatran, blood clotting
Biological sourceHomo sapiens (human)
More
Total number of polymer chains3
Total formula weight44937.87
Authors
Krishnaswamy, S.,Kumar, S. (deposition date: 2023-08-08, release date: 2024-05-01, Last modification date: 2024-10-16)
Primary citationYu, H.,Kumar, S.,Frederiksen, J.W.,Kolyadko, V.N.,Pitoc, G.,Layzer, J.,Yan, A.,Rempel, R.,Francis, S.,Krishnaswamy, S.,Sullenger, B.A.
Aptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors.
Nat Commun, 15:3977-3977, 2024
Cited by
PubMed Abstract: Potent and selective inhibition of the structurally homologous proteases of coagulation poses challenges for drug development. Hematophagous organisms frequently accomplish this by fashioning peptide inhibitors combining exosite and active site binding motifs. Inspired by this biological strategy, we create several EXACT inhibitors targeting thrombin and factor Xa de novo by linking EXosite-binding aptamers with small molecule ACTive site inhibitors. The aptamer component within the EXACT inhibitor (1) synergizes with and enhances the potency of small-molecule active site inhibitors by many hundred-fold (2) can redirect an active site inhibitor's selectivity towards a different protease, and (3) enable efficient reversal of inhibition by an antidote that disrupts bivalent binding. One EXACT inhibitor, HD22-7A-DAB, demonstrates extraordinary anticoagulation activity, exhibiting great potential as a potent, rapid onset anticoagulant to support cardiovascular surgeries. Using this generalizable molecular engineering strategy, selective, potent, and rapidly reversible EXACT inhibitors can be created against many enzymes through simple oligonucleotide conjugation for numerous research and therapeutic applications.
PubMed: 38730234
DOI: 10.1038/s41467-024-48211-6
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.207 Å)
Structure validation

227344

数据于2024-11-13公开中

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