PDBsum entry: 1ijk

Blood clotting/toxin

PDB-id

1ijk

	Biological unit* = asymmetric unit, as shown (as deduced by PQS*)


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Protein chains

Waters ×94

* Residue conservation analysis

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PDB id:

1ijk

Name:

Blood clotting/toxin

Title:

The von willebrand factor mutant (i546v) a1 domain- botrocetin complex

Structure:

Von willebrand factor. Chain: a. Fragment: a1 domain. Engineered: yes. Mutation: yes. Botrocetin. Chain: b. Fragment: a-subunit. Botrocetin.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Bothrops jararaca. Jararaca. Organism_taxid: 8724. Secretion: venom.

Biological unit:

Trimer (from PQS)

UniProt:

Chain A: P04275 (VWF_HUMAN)

Seq:

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Struc:


Seq:				2813 a.a.

Struc:				199 a.a.*

Chain B: P22029 (BOTA_BOTJA)

Seq:				133 a.a.

Struc:				133 a.a.

Chain C: P22030 (BOTB_BOTJA)

Seq:

125 a.a.

Struc:

119 a.a.

Key:		PfamA domain
		Secondary structure			CATH domain

* PDB and UniProt seqs differ at 1 residue position (black cross)

Resolution:

2.60Å

R-factor:

0.219

R-free:

0.279

Authors:

K.Fukuda,T.A.Doggett,L.A.Bankston,M.A.Cruz,T.G.Diacovo, R.C.Liddington

Key ref:

K.Fukuda et al. (2002). Structural basis of von Willebrand factor activation by the snake toxin botrocetin.. Structure, 10, 943-950. [PubMed id: 12121649] [DOI: 10.1016/S0969-2126(02)00787-6]

Date:

26-Apr-01

Release date:

10-Jul-02

Related entries:

1auq
1auq is the wild type a1 domain of von willebrand factor
1ijb
crystal structure of the mutant (i546v) a1 domain of the
von willebrand factor

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Key reference

DOI no: 10.1016/S0969-2126(02)00787-6 Structure 10:943-950 (2002)

PubMed id: 12121649

Structural basis of von Willebrand factor activation by the snake toxin botrocetin.

K.Fukuda, T.A.Doggett, L.A.Bankston, M.A.Cruz, T.G.Diacovo, R.C.Liddington.

ABSTRACT

The A1 domain of von Willebrand factor (vWF) mediates platelet adhesion to sites of vascular injury by binding to the platelet receptor glycoprotein Ib (GpIb), an interaction that is regulated by hydrodynamic shear forces. The GpIb binding surface of A1 is distinct from a regulatory region, suggesting that ligand binding is controlled allosterically. Here we report the crystal structures of the "gain-of-function" mutant A1 domain (I546V) and its complex with the exogenous activator botrocetin. We show that botrocetin switches the mutant A1 back toward the wild-type conformation, suggesting that affinity is enhanced by augmenting the GpIb binding surface rather than through allosteric control. Functional studies of platelet adhesion under flow further suggest that the activation mechanism is distinct from that of the gain-of-function mutation.

Selected figure(s)

Figure 3.
Figure 3. Structure of the A1-Botrocetin Complex(A) Stereo view (Ca tracing) of the complex. The current model includes 199 residues from 502 to 700 of the mutant A1 domain, 133 (119) residues of the a (b) subunits of botrocetin, and 94 water molecules. There is no electron density for the loop (residues 55-60 in the b subunit). The A1 domain is in blue; the a and b subunits of botrocetin are in pink and green, respectively. Gain-of-function mutations are shown as blue balls; loss-of-function mutations are shown in red; loss of botrocetin binding mutations are shown in yellow. The I546V mutation site is shown as a green ball.(B) Space-filling model of the complex with mutation sites indicated; same view as in (A). The NMC-4 antibody (V[H]-V[L] dimer) is shown as a semitransparent molecular surface.(C) Electrostatic surface potential contoured from -15 (red) to +15 (blue) kT e^ -1. The figure was made using RASTER3D [30] and GRASP [32].

The above figure is reprinted by permission from Cell Press: Structure (2002, 10, 943-950) copyright 2002.

Figure was selected by the author.

Literature references that cite this PDB file's key reference

PubMed id Reference

19698085 C.J.Severyn, U.Shinde, and P.Rotwein (2009).
Molecular biology, genetics and biochemistry of the repulsive guidance molecule family.

Biochem J, 422, 393-403.

16681634 D.J.Bowen, and P.W.Collins (2006).
Insights into von Willebrand factor proteolysis: clinical implications.

Br J Haematol, 133, 457-467.

15665869 K.Fukuda, T.Doggett, I.J.Laurenzi, R.C.Liddington, and T.G.Diacovo (2005).
The snake venom protein botrocetin acts as a biological brace to promote dysfunctional platelet aggregation.

Nat Struct Mol Biol, 12, 152-159.

PDB codes: 1u0n 1u0o

16102046 Q.Lu, J.M.Clemetson, and K.J.Clemetson (2005).
Snake venoms and hemostasis.

J Thromb Haemost, 3, 1791-1799.

14757772 A.Shimizu, T.Matsushita, T.Kondo, Y.Inden, T.Kojima, H.Saito, and M.Hirai (2004).
Identification of the amino acid residues of the platelet glycoprotein Ib (GPIb) essential for the von Willebrand factor binding by clustered charged-to-alanine scanning mutagenesis.

J Biol Chem, 279, 16285-16294.

15502319 G.Xu, M.Teng, L.Niu, P.Liu, Y.Dong, Q.Liu, Q.Huang, and Q.Hao (2004).
Purification, characterization, crystallization and preliminary X-ray crystallographic analysis of two novel C-type lectin-like proteins: Aall-A and Aall-B from Deinagkistrodon acutus venom.

Acta Crystallogr D Biol Crystallogr, 60, 2035-2037.

15039442 J.J.Dumas, R.Kumar, T.McDonagh, F.Sullivan, M.L.Stahl, W.S.Somers, and L.Mosyak (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.

PDB code: 1sq0

14684891 T.Batuwangala, M.Leduc, J.M.Gibbins, C.Bon, and E.Y.Jones (2004).
Structure of the snake-venom toxin convulxin.

Acta Crystallogr D Biol Crystallogr, 60, 46-53.

PDB code: 1uos

14580195 K.Horii, D.Okuda, T.Morita, and H.Mizuno (2003).
Structural characterization of EMS16, an antagonist of collagen receptor (GPIa/IIa) from the venom of Echis multisquamatus.

Biochemistry, 42, 12497-12502.

PDB code: 1ukm

12851390 N.Maita, K.Nishio, E.Nishimoto, T.Matsui, Y.Shikamoto, T.Morita, J.E.Sadler, and H.Mizuno (2003).
Crystal structure of von Willebrand factor A1 domain complexed with snake venom, bitiscetin: insight into glycoprotein Ibalpha binding mechanism induced by snake venom proteins.

J Biol Chem, 278, 37777-37781.

PDB code: 1uex

12579041 Z.M.Ruggeri (2003).
Von Willebrand factor.

Curr Opin Hematol, 10, 142-149.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.