Factor Xa: Difference between revisions
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The S3 site of factor Xa has little specificity; the side chain of the Asp 13 P3 residue protrudes out of the active site cleft. | The S3 site of factor Xa has little specificity; the side chain of the Asp 13 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" /> | <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" /> | ||
The cation-pi interaction is a strong, non-covalent bond formed by electrostatic interactions between the side chains of aromatic residues and various cations. These bonds are characterized by the fact that sp2 carbons are more electronegative then hydrogen, and 6 local Cδ- - Hδ+ bond dipoles are created around the benzene ring. Collectively, these dipoles create an accumulation of negative charge in the center of the ring and a belt of positive charge around the edge. This charge distribution allows for cation binding to the center of the ring, however, if the ring is not properly positioned, the cation will be repulsed by the positive charge of the outer ring. The S4 binding pocket of Factor Xa is formed from three aromatic residues, tyrosine 99, phenylalanine 174, tryptophan 215, sufficiently rich in properly positioned pi-electrons that it is not only a hydrophobic pocket, but also forms a cation recognition site. Many factor Xa inhibitors have a basic residue binding in this pocket, when protonated, cation-pi interactions are formed. | |||
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 | ||
