PDBsum entry 1p9a

Blood clotting

PDB id: 1p9a

Contents

Protein chain

266 a.a. *

Ligands

NAG-NAG-BMA-BMA

Waters ×207

* Residue conservation analysis

PDB id:

1p9a

Name:

Blood clotting

Title:

Crystal structure of n-terminal domain of human platelet receptor glycoprotein ib-alpha at 1.7 angstrom resolution

Structure:

Platelet glycoprotein ib alpha chain precursor. Chain: g. Fragment: n-terminal domain. Synonym: glycoprotein ibalpha, gp-ib alpha, gpiba, gpib-alpha, cd42b- alpha, cd42b, contains: glycocalicin. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: gp1ba. Expressed in: drosophila melanogaster. Expression_system_taxid: 7227.

Resolution:

1.70Å R-factor: 0.204 R-free: 0.224

Authors:

K.I.Varughese,R.Celikel,Z.M.Ruggeri

Key ref:

R.Celikel et al. (2003). Modulation of alpha-thrombin function by distinct interactions with platelet glycoprotein Ibalpha. Science, 301, 218-221. PubMed id: 12855810 DOI: 10.1126/science.1084183

Date:

09-May-03 Release date: 22-Jul-03

Protein chain

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

Seq: 652 a.a.

Struc: 266 a.a.*

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

DOI no: 10.1126/science.1084183

Science 301:218-221 (2003)

PubMed id: 12855810

Modulation of alpha-thrombin function by distinct interactions with platelet glycoprotein Ibalpha.

R.Celikel, R.A.McClintock, J.R.Roberts, G.L.Mendolicchio, J.Ware, K.I.Varughese, Z.M.Ruggeri.

ABSTRACT

Thrombin bound to platelets contributes to stop bleeding and, in pathological conditions, may cause vascular thrombosis. We have determined the structure of platelet glycoprotein Ibalpha (GpIbalpha) bound to thrombin at 2.3 angstrom resolution and defined two sites in GpIbalpha that bind to exosite II and exosite I of two distinct alpha-thrombin molecules, respectively. GpIbalpha occupancy may be sequential, as the site binding to alpha-thrombin exosite I appears to be cryptic in the unoccupied receptor but exposed when a first thrombin molecule is bound through exosite II. These interactions may modulate alpha-thrombin function by mediating GpIbalpha clustering and cleavage of protease-activated receptors, which promote platelet activation, while limiting fibrinogen clotting through blockade of exosite I.

Selected figure(s)

Figure 1.
Fig. 1. A stereo view of the interaction between GpIb N (red) and two -thrombin molecules. The interaction with thrombin I (blue) involves the anion-binding exosite I (Ex I); that with thrombin II (green), the anion-binding exosite II (Ex II). GpIb N residues participating in substantial interactions are shown in ball-and-stick representation (magenta). The catalytic triad (His57, Asp102, and Ser195) in each thrombin molecule is shown in red. The position of the inhibitor peptide, PPACK, is shown as a short arrow (gray). Thrombin I and thrombin II are related by crystallographic symmetry. Similarly, two symmetry-related GpIb N molecules interact with exosite I and exosite II of the same thrombin, suggesting a potential mode for cross-linking of GpIb on the platelet surface. The figure was produced with the program Molscript (29).

Figure 3.
Fig. 3. Schematic drawing of the proposed sequential mode of -thrombin binding to platelets. In unoccupied GpIb , the site interacting with -thrombin exosite II is exposed and that interacting with exosite I is cryptic. Thus, the interaction always initiates with GpIb binding to exosite II of an -thrombin molecule; then, a second -thrombin can bind through exosite I. When the latter interaction takes place, fibrinogen clotting is impaired (noted by an x on -thrombin).Subsequent dissociation or new associations create the possibility for several different complex forms between GpIb and -thrombin, some of which are shown here. It is assumed that the interaction mediated through -thrombin exosite I is more stable than that through exosite II. On the platelet surface, where GpIb is membrane-bound, one -thrombin molecule can cross-link two adjacent receptors.

The above figures are reprinted by permission from the AAAs: Science (2003, 301, 218-221) copyright 2003.

Figures were selected by the author.

Author's comment

Additional experiments have demonstrated that alpha-thrombin in solution at physiologic concentrations interacts with GP Ib-alpha through exosite I and exosite II. Such a finding proves that the two-site interaction may be functionally relevant and is not a consequence of crystal packing.
Zaverio M. Ruggeri