Factor Xa: Difference between revisions

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The factor Xa heavy chain contains the activation peptide and trypsin-like serine protease domain
The factor Xa heavy chain contains the activation peptide and trypsin-like serine protease domain


===Catalytic Triad===
====Substrate Recognition Sites ====
<applet load='2PR3' size='300' frame='true' align='right' caption='Structure of factor Xa PBD id: 2PR3' />
Serine proteases use a His57, Asp102, Ser195 [http://en.wikipedia.org/wiki/Catalytic_triad catalytic triad], each playing an important role. The serine donates an OH group to act as a nucleophile and attack the carbonyl group of the peptide bond that will be broken within the substrate. Histidine coordinates the attack of the peptide bond by accepting the hydrogen from the serine –OH group with a pair of electrons on nitrogen. Aspartate contains a carboxyl group that aids in proper positioning of the histidine and stabilization, through hydrogen bonding.
 
===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. Arg15 binds in the S1 pocket, Gly14 binds the S2 pocket. Ile binds the S4 pocket. The <scene name='Factor_Xa/Transparent_-_no_inhib_-_s1/3'>S1 pocket</scene> determines binding selectivity for factor Xa. The S1 pocket is formed by loops in residues 214-220 and 189-195 that are linked by a Cys220-Cys191 disulfide bond. Residues 225-228 form the lower portion of the pocket.<ref>Factor X. Wikipedia</ref> The <scene name='Factor_Xa/Transparent_-_no_inhib_-oxy_ho/1'>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. Arg15 binds in the S1 pocket, Gly14 binds the S2 pocket. Ile binds the S4 pocket. The <scene name='Factor_Xa/Transparent_-_no_inhib_-_s1/3'>S1 pocket</scene> determines binding selectivity for factor Xa. The S1 pocket is formed by loops in residues 214-220 and 189-195 that are linked by a Cys220-Cys191 disulfide bond. Residues 225-228 form the lower portion of the pocket.<ref>Factor X. Wikipedia</ref> The <scene name='Factor_Xa/Transparent_-_no_inhib_-oxy_ho/1'>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" />


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<scene name='Factor_Xa/Transparent_-_no_inhib_s4/1'>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/3'>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/2'>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/2'>water site</scene> is composed of  the hydrophobic side chains of Thr98, Ile175 and Thr177 and traps a water molecule. <ref name="Inhib" />
<scene name='Factor_Xa/Transparent_-_no_inhib_s4/1'>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/3'>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/2'>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/2'>water site</scene> is composed of  the hydrophobic side chains of Thr98, Ile175 and Thr177 and traps a water molecule. <ref name="Inhib" />


===Helix capping ===
====Catalytic Triad====
<applet load='2PR3' size='300' frame='true' align='right' caption='Structure of factor Xa PBD id: 2PR3' />
Serine proteases use a His57, Asp102, Ser195 [http://en.wikipedia.org/wiki/Catalytic_triad catalytic triad], each playing an important role. The serine donates an OH group to act as a nucleophile and attack the carbonyl group of the peptide bond that will be broken within the substrate. Histidine coordinates the attack of the peptide bond by accepting the hydrogen from the serine –OH group with a pair of electrons on nitrogen. Aspartate contains a carboxyl group that aids in proper positioning of the histidine and stabilization, through hydrogen bonding.
 
====Helix capping ====
Helices have exposed hydrogen bond donors from the first 4 residues at the N-terminus. Helix capping refers to H-bonding to these groups, primarily by nearby side chains, to "seal" the helix. Factor Xa forms a helix from residue 165-171 that is capped at the N-terminus by an aspartate residue number 164. The aspartate side chain is twisted to follow the helix and provide capping. The backbone carbonyl is hydrogen bonded to the backbone nitrogen groups of serine 167 and cysteine 168.  One of the side chain oxygen groups of aspartate forms hydrogen bonds with the backbone nitrogen groups of asparagine 166 and serine 167. Arginine 165 is the first residue in the helix and it provides capping hydrogen bonds for lysine 169. The backbone nitrogen group of arginine 165 appears to form a hydrogen bond with the solvent. The aspartate and asparagine residues 164 and 165 provide capping hydrogen bonds for the hydrogen bond donors of the first 4 N-terminal helix residues.
Helices have exposed hydrogen bond donors from the first 4 residues at the N-terminus. Helix capping refers to H-bonding to these groups, primarily by nearby side chains, to "seal" the helix. Factor Xa forms a helix from residue 165-171 that is capped at the N-terminus by an aspartate residue number 164. The aspartate side chain is twisted to follow the helix and provide capping. The backbone carbonyl is hydrogen bonded to the backbone nitrogen groups of serine 167 and cysteine 168.  One of the side chain oxygen groups of aspartate forms hydrogen bonds with the backbone nitrogen groups of asparagine 166 and serine 167. Arginine 165 is the first residue in the helix and it provides capping hydrogen bonds for lysine 169. The backbone nitrogen group of arginine 165 appears to form a hydrogen bond with the solvent. The aspartate and asparagine residues 164 and 165 provide capping hydrogen bonds for the hydrogen bond donors of the first 4 N-terminal helix residues.


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