7A6O
Crystal Structure of the Complex of the Recombinant Von Willebrand Factor AIM-A1 domain and VHH81 at 2.1 Angstrom resolution
Summary for 7A6O
| Entry DOI | 10.2210/pdb7a6o/pdb |
| Descriptor | von Willebrand factor, VHH81 Nanobody fragment, SULFATE ION, ... (4 entities in total) |
| Functional Keywords | thrombosis von willebrand factor a1 aim-a1 blood clotting complex vwf, blood clotting |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 37399.70 |
| Authors | Brown, A.K.,Emsley, J. (deposition date: 2020-08-25, release date: 2021-03-03, Last modification date: 2024-11-20) |
| Primary citation | Arce, N.A.,Cao, W.,Brown, A.K.,Legan, E.R.,Wilson, M.S.,Xu, E.R.,Berndt, M.C.,Emsley, J.,Zhang, X.F.,Li, R. Activation of von Willebrand factor via mechanical unfolding of its discontinuous autoinhibitory module. Nat Commun, 12:2360-2360, 2021 Cited by PubMed Abstract: Von Willebrand factor (VWF) activates in response to shear flow to initiate hemostasis, while aberrant activation could lead to thrombosis. Above a critical shear force, the A1 domain of VWF becomes activated and captures platelets via the GPIb-IX complex. Here we show that the shear-responsive element controlling VWF activation resides in the discontinuous autoinhibitory module (AIM) flanking A1. Application of tensile force in a single-molecule setting induces cooperative unfolding of the AIM to expose A1. The AIM-unfolding force is lowered by truncating either N- or C-terminal AIM region, type 2B VWD mutations, or binding of a ristocetin-mimicking monoclonal antibody, all of which could activate A1. Furthermore, the AIM is mechanically stabilized by the nanobody that comprises caplacizumab, the only FDA-approved anti-thrombotic drug to-date that targets VWF. Thus, the AIM is a mechano-regulator of VWF activity. Its conformational dynamics may define the extent of VWF autoinhibition and subsequent activation under force. PubMed: 33883551DOI: 10.1038/s41467-021-22634-x PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.117 Å) |
Structure validation
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