Factor Xa: Difference between revisions
From Proteopedia
Jump to navigationJump to search
| Line 20: | Line 20: | ||
The members of the trypsin-like serine protease family have two homologous greek key β-barrel subdomains (<scene name='Factor_Xa/Transparent_-no_inhib-_barrel1/1'>barrel 1</scene>, <scene name='Factor_Xa/Transparent_-_no_inhib_barrel2/1'>barrel 2</scene>) in the heavy chain. The greek key barrel is characterized as an up and down β-barrel with an n+3 linkage across the barrel, in this case, the across barrel linkage is an α-helix. The <scene name='Factor_Xa/Transparent_-no_inhib-_barrels/1'>two barrels</scene> pack together asymmetrically to constitute the compact <scene name='Factor_Xa/Transparent_-_barrels_catalyt/1'>catalytic domain</scene> (see below for more information). Although the hydrophobic core structures remain conserved throughout the family (12), considerable variation is seen in the surface loops, especially surrounding the active site where they determine substrate specificities. <ref>PMID: 9707558</ref> | The members of the trypsin-like serine protease family have two homologous greek key β-barrel subdomains (<scene name='Factor_Xa/Transparent_-no_inhib-_barrel1/1'>barrel 1</scene>, <scene name='Factor_Xa/Transparent_-_no_inhib_barrel2/1'>barrel 2</scene>) in the heavy chain. The greek key barrel is characterized as an up and down β-barrel with an n+3 linkage across the barrel, in this case, the across barrel linkage is an α-helix. The <scene name='Factor_Xa/Transparent_-no_inhib-_barrels/1'>two barrels</scene> pack together asymmetrically to constitute the compact <scene name='Factor_Xa/Transparent_-_barrels_catalyt/1'>catalytic domain</scene> (see below for more information). Although the hydrophobic core structures remain conserved throughout the family (12), considerable variation is seen in the surface loops, especially surrounding the active site where they determine substrate specificities. <ref>PMID: 9707558</ref> | ||
====Substrate Recognition Sites ==== | ====Substrate Recognition Sites ==== | ||
The natural substrate of factor Xa is prothromin, which is cleaved after the arginine in the sequence: Ile12-Asp13-Gly14-Arg15-Ile16- Val17-Glu18-Gly19. Arg 15 binds in the S1 pocket, Gly 14 binds the S2 pocket, Ile binds the S4 pocket. The <scene name='Factor_Xa/Transparent_-_no_inhib_-_s1/7'>S1 pocket</scene>, is located next to the catalytic triad, and is formed by loops in residues 214-220 and 189-195 that are linked by a <scene name='Factor_Xa/Transparent_-_no_inhib_-_s1/6'>Cys 220-Cys 191</scene> disulfide bond . Residues 225-228 form the lower portion of the pocket.<ref>Factor X. Wikipedia</ref> The S1 pocket binding selectivity is determined by residues Asp 189, Gly 216, and Gly 226. Asp 189 (R-group pKa: 12.48) most likely forms electrostatic interactions with the S1' Arg 15 (R-group pKa: 4). The <scene name='Factor_Xa/Transparent_-_no_inhib_oxianio/3'>oxyanion hole</scene> is formed by the backbone amides of Gly193 and Ser195.<ref name="ser wiki">Serine Protease. Wikipedia</ref> The oxyanion hole uses its main chain amide groups to stabilize the tetrahedral intermediate.<ref name="specificity" /> | |||
<applet load='2PR3' size='300' frame='true' align='right' caption='Structure of factor Xa PBD id: 2PR3' /> | <applet load='2PR3' size='300' frame='true' align='right' caption='Structure of factor Xa PBD id: 2PR3' /> | ||
The <scene name='Factor_Xa/Transparent_-_no_inhib_-_s2/3'>S2 site</scene> of factor Xa is formed by the 90s loop which is positioned adjacent to His 57. Consistent with Gly 14 as the P2 element in prothrombin, S2 is a small, shallow pocket.<ref name="Inhib">PMID: 11172669</ref> | The <scene name='Factor_Xa/Transparent_-_no_inhib_-_s2/3'>S2 site</scene> of factor Xa is formed by the 90s loop which is positioned adjacent to His 57. Consistent with Gly 14 as the P2 element in prothrombin, S2 is a small, shallow pocket.<ref name="Inhib">PMID: 11172669</ref> | ||
