6NAN
NMR structure determination of Ixolaris and Factor X interaction reveals a noncanonical mechanism of Kunitz inhibition
Summary for 6NAN
| Entry DOI | 10.2210/pdb6nan/pdb |
| NMR Information | BMRB: 27051 |
| Descriptor | Ixolaris (1 entity in total) |
| Functional Keywords | coagulation blood inhibitor, factor xa, tissue factor, tick saliva, blood clotting |
| Biological source | Ixodes scapularis (Black-legged tick) |
| Total number of polymer chains | 1 |
| Total formula weight | 15753.25 |
| Authors | De Paula, V.S.,Sgourakis, N.G.,Francischetti, I.M.B.,Almeida, F.C.L.,Monteiro, R.Q.,Valente, A.P. (deposition date: 2018-12-06, release date: 2019-06-12, Last modification date: 2024-10-16) |
| Primary citation | De Paula, V.S.,Sgourakis, N.G.,Francischetti, I.M.B.,Almeida, F.C.L.,Monteiro, R.Q.,Valente, A.P. NMR structure determination of Ixolaris and factor X(a) interaction reveals a noncanonical mechanism of Kunitz inhibition. Blood, 134:699-708, 2019 Cited by PubMed Abstract: Ixolaris is a potent tick salivary anticoagulant that binds coagulation factor Xa (FXa) and zymogen FX, with formation of a quaternary tissue factor (TF)/FVIIa/ FX(a)/Ixolaris inhibitory complex. Ixolaris blocks TF-induced coagulation and PAR2 signaling and prevents thrombosis, tumor growth, and immune activation. We present a high-resolution structure and dynamics of Ixolaris and describe the structural basis for recognition of FX. Ixolaris consists of 2 Kunitz domains (K1 and K2) in which K2 is strikingly dynamic and encompasses several residues involved in FX binding. This indicates that the backbone plasticity of K2 is critical for Ixolaris biological activity. Notably, a nuclear magnetic resonance-derived model reveals a mechanism for an electrostatically guided, high-affinity interaction between Ixolaris and FX heparin-binding (pro)exosite, resulting in an allosteric switch in the catalytic site. This is the first report revealing the structure-function relationship of an anticoagulant targeting a zymogen serving as a scaffold for TF inhibition. PubMed: 31133602DOI: 10.1182/blood.2018889493 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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