4BQD

KD1 of human TFPI in complex with a synthetic peptide

4BQD の概要

• エントリーDOI: 10.2210/pdb4bqd/pdb
• 分子名称: TISSUE FACTOR PATHWAY INHIBITOR (LIPOPROTEIN-ASSOCIATED COAGULATION INHIBITOR) VARIANT, PEPTIDE, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: blood clotting
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 23468.56

構造登録者

Griessner, A.,Brandstetter, H. (登録日: 2013-05-30, 公開日: 2013-12-04, 最終更新日: 2025-04-09)

主引用文献

Dockal, M.,Hartman, R.,Fries, M.,Christella, M.,Thomassen, L.G.D.,Heizman, A.,Ehrlich, H.,Rosing, J.,Osterkamp, F.,Polakowski, T.,Reineke, U.,Griessner, A.,Brandstetter, H.,Scheiflinger, F.
Small Peptides Blocking Inhibition of Factor Xa and Tissue Factor-Factor Viia by Tissue Factor Pathway Inhibitor (Tfpi)
J.Biol.Chem., 289:1732-, 2014

PubMed Abstract: Tissue factor pathway inhibitor (TFPI) is a Kunitz-type protease inhibitor that inhibits activated factor X (FXa) via a slow-tight binding mechanism and tissue factor-activated FVII (TF-FVIIa) via formation of a quaternary FXa-TFPI-TF-FVIIa complex. Inhibition of TFPI enhances coagulation in hemophilia models. Using a library approach, we selected and subsequently optimized peptides that bind TFPI and block its anticoagulant activity. One peptide (termed compound 3), bound with high affinity to the Kunitz-1 (K1) domain of TFPI (Kd ∼1 nM). We solved the crystal structure of this peptide in complex with the K1 of TFPI at 2.55-Å resolution. The structure of compound 3 can be segmented into a N-terminal anchor; an Ω-shaped loop; an intermediate segment; a tight glycine-loop; and a C-terminal α-helix that is anchored to K1 at its reactive center loop and two-stranded β-sheet. The contact surface has an overall hydrophobic character with some charged hot spots. In a model system, compound 3 blocked FXa inhibition by TFPI (EC50 = 11 nM) and inhibition of TF-FVIIa-catalyzed FX activation by TFPI (EC50 = 2 nM). The peptide prevented transition from the loose to the tight FXa-TFPI complex, but did not affect formation of the loose FXa-TFPI complex. The K1 domain of TFPI binds and inhibits FVIIa and the K2 domain similarly inhibits FXa. Because compound 3 binds to K1, our data show that K1 is not only important for FVIIa inhibition but also for FXa inhibition, i.e. for the transition of the loose to the tight FXa-TFPI complex. This mode of action translates into normalization of coagulation of hemophilia plasmas. Compound 3 thus bears potential to prevent bleeding in hemophilia patients.

PubMed: 24275667
DOI: 10.1074/JBC.M113.533836

実験手法

X-RAY DIFFRACTION (2.48 Å)