PDBsum entry 1sq0

Blood clotting

PDB id: 1sq0

Contents

Protein chains

198 a.a. *

265 a.a. *

Waters ×318

* Residue conservation analysis

PDB id:

1sq0

Name:

Blood clotting

Title:

Crystal structure of the complex of the wild-type von willebrand factor a1 domain and glycoprotein ib alpha at 2.6 angstrom resolution

Structure:

Von willebrand factor (vwf) [contains: von willebrand antigen ii]. Chain: a. Fragment: a1. Engineered: yes. Platelet glycoprotein ib alpha chain (glycoprotein ibalpha) (gp-ib alpha) (gpiba) (gpib-alpha) (cd42b-alpha) (cd42b) [contains: glycocalicin]. Chain: b.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: vwf, f8vwf. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Gene: gp1ba. Expressed in: cricetulus griseus. Expression_system_taxid: 10029.

Biol. unit:

Dimer (from PQS)

Resolution:

2.60Å R-factor: 0.190 R-free: 0.239

Authors:

J.J.Dumas,R.Kumar,T.Mcdonagh,F.Sullivan,M.L.Stahl,W.S.Somers,L.Mosyak

Key ref:

J.J.Dumas et al. (2004). Crystal structure of the wild-type von Willebrand factor A1-glycoprotein Ibalpha complex reveals conformation differences with a complex bearing von Willebrand disease mutations. J Biol Chem, 279, 23327-23334. PubMed id: 15039442 DOI: 10.1074/jbc.M401659200

Date:

17-Mar-04 Release date: 13-Apr-04

Protein chain

P04275  (VWF_HUMAN) -  von Willebrand factor from Homo sapiens

Seq: 2813 a.a.

Struc: 198 a.a.*

Protein chain

P07359  (GP1BA_HUMAN) -  Platelet glycoprotein Ib alpha chain from Homo sapiens

Seq: 652 a.a.

Struc: 265 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

DOI no: 10.1074/jbc.M401659200

J Biol Chem 279:23327-23334 (2004)

PubMed id: 15039442

Crystal structure of the wild-type von Willebrand factor A1-glycoprotein Ibalpha complex reveals conformation differences with a complex bearing von Willebrand disease mutations.

J.J.Dumas, R.Kumar, T.McDonagh, F.Sullivan, M.L.Stahl, W.S.Somers, L.Mosyak.

ABSTRACT

The adhesion of platelets to the subendothelium of blood vessels at sites of vascular injury under high shear conditions is mediated by a direct interaction between the platelet receptor glycoprotein Ibalpha (GpIbalpha) and the A1 domain of the von Willebrand factor (VWF). Here we report the 2.6-A crystal structure of a complex comprised of the extracellular domain of GpIbalpha and the wild-type A1 domain of VWF. A direct comparison of this structure to a GpIbalpha-A1 complex containing "gain-of-function" mutations, A1-R543Q and GpIbalpha-M239V, reveals specific structural differences between these complexes at sites near the two GpIbalpha-A1 binding interfaces. At the smaller interface, differences in interaction show that the alpha1-beta2 loop of A1 serves as a conformational switch, alternating between an open alpha1-beta2 isomer that allows faster dissociation of GpIbalpha-A1, as observed in the wild-type complex, and an extended isomer that favors tight association as seen in the complex containing A1 with a type 2B von Willebrand Disease (VWD) mutation associated with spontaneous binding to GpIbalpha. At the larger interface, differences in interaction associated with the GpIbalpha-M239V platelet-type VWD mutation are minor and localized but feature discrete gamma-turn conformers at the loop end of the beta-hairpin structure. The beta-hairpin, stabilized by a strong classic gamma-turn as seen in the mutant complex, relates to the increased affinity of A1 binding, and the beta-hairpin with a weak inverse gamma-turn observed in the wild-type complex corresponds to the lower affinity state of GpIbalpha. These findings provide important details that add to our understanding of how both type 2B and platelet-type VWD mutations affect GpIbalpha-A1 binding affinity.

Selected figure(s)

Figure 2.
FIG. 2. Superposition of GpIb -A1 and GpIb -M239V/A1-R543Q complexes. The GpIb is green, and the GpIb -bound wild-type A1 domain is gold. Regions of GpIb -M239V that differ most extensively from wild-type A1 are red ( -switch region, Val227-Ser241; cysteine loop, Asp249-Phe^254) and the remainder of the molecule is white. The region of A1-R543Q with the most notable change in conformation compared with the wild-type A1 structure is blue ( 1- 2 loop, Arg543-Arg552), and the remainder of A1 is white. The structure of mutant complex is derived from PDB code 1M10 [PDB] (35).

Figure 5.
FIG. 5. Superposition of unliganded A1, wild-type GpIb -A1 and GpIb -M239V-A1-R543Q. Rearrangement of the 1- 2 loop region of A1 is highlighted. The 1- 2 loop region of unliganded A1 (33)(shown in purple) adopts an intermediate conformation between the closed conformation of 1- 2 in the mutant complex (blue) and the open conformation of 1- 2 in the wild-type complex (gold).

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 23327-23334) copyright 2004.

Figures were selected by the author.