Factor Xa: Difference between revisions
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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" /> | 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" /> | ||
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 | 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> | ||
<scene name='Factor_Xa/Transparent_-_no_inhib_s4/2'>S4 pocket</scene> is formed between the 90s and 170s loops and binds an Ile. This region contains 3 ligand binding domains. The <scene name='Factor_Xa/Transparent_-_no_inhib_phob_bo/4'>hydrophobic box</scene> is located at the entrance to S4 and contains Phe174, Tyr99 and Trp215, which form a deep aryl-binding pocket. The <scene name='Factor_Xa/Transparent_-_no_inhib_oxianio/3'>cationic hole</scene> is formed by the backbone carbonyl and side chain of Glu97 and the backbone carbonyl of Lys96. The <scene name='Factor_Xa/Transparent_-_no_inhib-_h2o_si/3'>water site</scene> is composed of the hydrophillic side chains of Thr98, Ile175 and Thr177 and traps a water molecule. <ref name="Inhib" /> | The S3 site of factor Xa has little specificity; the side chain of the Asp 113 P3 residue protrudes out of the active site cleft. | ||
<scene name='Factor_Xa/Transparent_-_no_inhib_s4/2'>S4 pocket</scene> is formed between the 90s and 170s loops and binds an Ile 12. This region contains 3 ligand binding domains. The <scene name='Factor_Xa/Transparent_-_no_inhib_phob_bo/4'>hydrophobic box</scene> is located at the entrance to S4 and contains Phe174, Tyr99 and Trp215, which form a deep aryl-binding pocket. The <scene name='Factor_Xa/Transparent_-_no_inhib_oxianio/3'>cationic hole</scene> is formed by the backbone carbonyl and side chain of Glu97 and the backbone carbonyl of Lys96. The <scene name='Factor_Xa/Transparent_-_no_inhib-_h2o_si/3'>water site</scene> is composed of the hydrophillic side chains of Thr98, Ile175 and Thr177 and traps a water molecule. <ref name="Inhib" /> | |||
Hydrogen bonds form between the carbonyl oxygen of Ser214 and the NH of the P1 (Arg 14) residue, the NH of | Hydrogen bonds form between the carbonyl oxygen of Ser214 and the NH of the P1 (Arg 14) residue, the NH of | ||
