Sandbox Reserved 1493: Difference between revisions

''Jmol displays residues 32-483 of αIIb and residues 27-487 of β3. In order to have a global view of the integrin, refer to pictures.''

The extracellular N-Terminus forms a cap over the '''β-propeller''' domain which is folded by seven successive blades of aminoterminal repeats. Each blade is a β-hairpin loop-like structure composed of 4 antiparallel β strands located in each repeat and connected by loops of the surface. This β-propeller is linked to a '''thigh''' and '''two calf''' domains, which form the leg structure that supports the heavy head. The total forms the stalk of the αIIb subunit. The knee of the subunit between the thigh and the first calf domain is the site at which the head bends (inactivated form of the integrin.

Its '''stalk''' is mainly composed of a plexin-sempahorin-integrin (PSI) domain and a '''hybrid domain'''. A <scene name='80/802667/Beta_head_cysteines_core/1'>cysteine-rich core</scene> ''(Cys displayed in purple, disulfide bonds in yellow)'' occupies the stalk of β3 from residues 400 to 650. Other cysteins links the N-terminal of the protein to the β I domain thanks to a long-range disulfide bond. <scene name='80/802667/Beta_head_cysteines/1'>Cysteines</scene> of the extracellular domain of the β subunit are thought to have a role in the activation of the headpiece.

4 principal '''ligand binding domains''' involved in clotting have been characterized on the extracellular '''headpiece''' of the integrin at the <scene name='80/802667/2vdo_ligand_in_active_site/1'>interface</scene> between the αIIb subunit β propeller and the β3 subunit I domain.  

On stimulated platelets, αIIbβ3 has a highly specific receptor for the plasma protein '''fibrinogen'''. The '''KQAGDV binding site''' interacts with the fibrinogen γ-chain C terminus at the <scene name='80/802667/Fibrinogen_gamma_c_from_2vdo/4'>γHHLGGAKQAGDV sequence</scene> (residues 400 to 411 of γC). <scene name='80/802667/Fibrinogen_gamma_c_kqagd/3'>KQAGD</scene> is the minimal binding motif for αIIbβ3. The <scene name='80/802667/2vdo_asp_mg/3'>Asp side chain interacts with Mg2+</scene> (MIDAS) and the Gly residue enters in a pocket between the two subunits. The peptide of the ligand extends on a large active site on the integrin and has a turn in the backbone that leads the Lys side chain of the KQAGdV sequence into a pocket, so that its ammonium group is involved in hydrogen bonding with the αIIb subunit.

It opens a hinge in the integrin which triggers a very quick succession of subunit shifts transmitted from the tail to the extracellular headpiece across the transmembrane domain ('''inside-out signaling'''). Movements of helices and loops move the headpiece to an '''extended conformation''' which uncovers the interface between the two subunits containing '''ligand binding sites'''. Integrin is at an '''intermediate affinity state''' (extended conformation, closed headpiece) and can bind ligands.

Extracellular proteins such as fibrinogen then enables '''platelets aggregation''' and '''clotting'''. Integrin αIIbβ3 also bridges to other αIIbβ3 of adjacent platelets.

αIIbβ3 is a target of '''blocker drugs''' such as Abciximab (chimeric Fab fragment), <scene name='80/802667/2vdn_epti/1'>Eptifibatide</scene> (synthetic peptide inhibitor) and Tirofiban (synthetic non-peptide inhibitor). Such antagonists inhibit the binding of ligands to αIIbβ3 and thus platelet aggregation.

Displays of fibrinogen and Eptifibatide ligands are made thanks to 2VDO and 2VDN.