2H9E

Crystal Structure of FXa/selectide/NAPC2 ternary complex

Summary for 2H9E

• Entry DOI: 10.2210/pdb2h9e/pdb
• Descriptor: Coagulation factor X heavy chain, Coagulation factor X light chain, Anti-coagulant protein C2, ... (8 entities in total)
• Functional Keywords: factor xa, napc2, selectide, hydrolase-hydrolase inhibitor complex, blood clotting, hydrolase/hydrolase inhibitor
• Biological source: Ancylostoma caninum (dog hookworm); More
• Cellular location: Secreted: P00742 P00742
• Total number of polymer chains: 4
• Total formula weight: 53804.25

Authors

Murakami, M.T.,Geiger, G.,Tulinsky, A.,Arni, R.K. (deposition date: 2006-06-09, release date: 2007-02-13, Last modification date: 2017-10-18)

Primary citation

Murakami, M.T.,Rios-Steiner, J.,Weaver, S.E.,Tulinsky, A.,Geiger, J.H.,Arni, R.K.
Intermolecular Interactions and Characterization of the Novel Factor Xa Exosite Involved in Macromolecular Recognition and Inhibition: Crystal Structure of Human Gla-domainless Factor Xa Complexed with the Anticoagulant Protein NAPc2 from the Hematophagous Nematode Ancylostoma caninum.
J.Mol.Biol., 366:602-610, 2007

PubMed Abstract: NAPc2, an anticoagulant protein from the hematophagous nematode Ancylostoma caninum evaluated in phase-II/IIa clinical trials, inhibits the extrinsic blood coagulation pathway by a two step mechanism, initially interacting with the hitherto uncharacterized factor Xa exosite involved in macromolecular recognition and subsequently inhibiting factor VIIa (K(i)=8.4 pM) of the factor VIIa/tissue factor complex. NAPc2 is highly flexible, becoming partially ordered and undergoing significant structural changes in the C terminus upon binding to the factor Xa exosite. In the crystal structure of the ternary factor Xa/NAPc2/selectide complex, the binding interface consists of an intermolecular antiparallel beta-sheet formed by the segment of the polypeptide chain consisting of residues 74-80 of NAPc2 with the residues 86-93 of factor Xa that is additional maintained by contacts between the short helical segment (residues 67-73) and a turn (residues 26-29) of NAPc2 with the short C-terminal helix of factor Xa (residues 233-243). This exosite is physiologically highly relevant for the recognition and inhibition of factor X/Xa by macromolecular substrates and provides a structural motif for the development of a new class of inhibitors for the treatment of deep vein thrombosis and angioplasty.

PubMed: 17173931
DOI: 10.1016/j.jmb.2006.11.040

Experimental method

X-RAY DIFFRACTION (2.2 Å)