Factor Xa: Difference between revisions
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'''Factor Xa''', along with [http://en.wikipedia.org/wiki/Factor_va factor Va], calcium, and a phospholipid membrane surface to form the [http://en.wikipedia.org/wiki/Prothrombinase prothrombinase complex], and cleave [http://en.wikipedia.org/wiki/Prothrombin prothrombin] to its active form, [http://en.wikipedia.org/wiki/Prothrombin thrombin].<ref name="Greer" /> | '''Factor Xa''', along with [http://en.wikipedia.org/wiki/Factor_va factor Va], calcium, and a phospholipid membrane surface to form the [http://en.wikipedia.org/wiki/Prothrombinase prothrombinase complex], and cleave [http://en.wikipedia.org/wiki/Prothrombin prothrombin] to its active form, [http://en.wikipedia.org/wiki/Prothrombin thrombin].<ref name="Greer" /> | ||
==Relevance== | |||
Factor Xa is inhibited by [[Apixaban]] and [[Rivaroxaban]] which are anticoagulant medications. See also [[Anticoagulants]]. | |||
==Structure== | ==Structure== | ||
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====Low Barrier Hydrogen Bonds==== | ====Low Barrier Hydrogen Bonds==== | ||
< | <scene name='Factor_Xa/Lbhb/1'>Possible LBHB between His57 and Asp102</scene>. The mechanism by which the transition state is stabilized has been the topic of recent debate. Some groups suggest that His57 and Asp102 form and especially strong hydrogen bond, called a [http://en.wikipedia.org/wiki/Low-barrier_hydrogen_bond low barrier hydrogen bond (LBHB)]. They hypothesize that this hydrogen bond could promote formation of the transition state by stabilizing the Asp –His association and enhancing the bascisity of His57. <ref> PMID: 7661899</ref> <ref name="Frey alone">Frey, Perry A. Strong hydrogen bonding in chymotrypsin and other serine proteases. Journal of Physical Organic Chemistry (2004), 17(6-7), 511-520. </ref> This would enhance catalysis in the first step of the reaction. Formation of a LBHB requires a ΔpKa of approximately zero and a donor-to-acceptor distance of less then 2.65 Å for a nitrogen-oxygen pair like His57 and Asp102. Unlike a standard hydrogen bond, in which the hydrogen is located on the donor atom, a hydrogen in a LBHB is located equidistant between the 2 atoms. <ref name="subang"> PMID: 16834383 </ref> In 1998 Kuhn and colleagues published a crystal structure of ''Bacillus lentus'' subtilisn, another serine proetase, with 0.78 Å resolution at pH 5.9. The structure showed a distance of approximately 2.62 Å between the His57 nitrogen and the Asp102 oxygen, suggesting a LBHB. <ref> PMID: 9753430 </ref> | ||
The mechanism by which the transition state is stabilized has been the topic of recent debate. Some groups suggest that His57 and Asp102 form and especially strong hydrogen bond, called a [http://en.wikipedia.org/wiki/Low-barrier_hydrogen_bond low barrier hydrogen bond (LBHB)]. They hypothesize that this hydrogen bond could promote formation of the transition state by stabilizing the Asp –His association and enhancing the bascisity of His57. <ref> PMID: 7661899</ref> <ref name="Frey alone">Frey, Perry A. Strong hydrogen bonding in chymotrypsin and other serine proteases. Journal of Physical Organic Chemistry (2004), 17(6-7), 511-520. </ref> This would enhance catalysis in the first step of the reaction. Formation of a LBHB requires a ΔpKa of approximately zero and a donor-to-acceptor distance of less then 2.65 Å for a nitrogen-oxygen pair like His57 and Asp102. Unlike a standard hydrogen bond, in which the hydrogen is located on the donor atom, a hydrogen in a LBHB is located equidistant between the 2 atoms. <ref name="subang"> PMID: 16834383 </ref> In 1998 Kuhn and colleagues published a crystal structure of ''Bacillus lentus'' subtilisn, another serine proetase, with 0.78 Å resolution at pH 5.9. The structure showed a distance of approximately 2.62 Å between the His57 nitrogen and the Asp102 oxygen, suggesting a LBHB. <ref> PMID: 9753430 </ref> | |||
A more recent crystal structure of α-Lytic protease, published in 2006 with 0.82 Å resolution argues against both the his flip mechanism and the presence of a LBHB between His57 and Asp102 (2.755 Å in this structure). Fuhrmann ''et al'' suggests that a LBHB may have been present in the subtilisin strucutre, it is not required for the serine protease mechanism. Instead they state that the chymotrypsin-like proteases may use a network of optimized hydrogen bonds to position the stabilize the tetrahedral intermediate and position the catalytic triad. Ser195 undergoes a shift of ~1Å upon protonation of His57 that destabilizes the His57-Ser195 H-bond. This conformation change would prevent His57 from reprotonating Ser195 leading to regeneration of the substrate.<ref name="subang" /> | A more recent crystal structure of α-Lytic protease, published in 2006 with 0.82 Å resolution argues against both the his flip mechanism and the presence of a LBHB between His57 and Asp102 (2.755 Å in this structure). Fuhrmann ''et al'' suggests that a LBHB may have been present in the subtilisin strucutre, it is not required for the serine protease mechanism. Instead they state that the chymotrypsin-like proteases may use a network of optimized hydrogen bonds to position the stabilize the tetrahedral intermediate and position the catalytic triad. Ser195 undergoes a shift of ~1Å upon protonation of His57 that destabilizes the His57-Ser195 H-bond. This conformation change would prevent His57 from reprotonating Ser195 leading to regeneration of the substrate.<ref name="subang" /> | ||
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**[[1c5m]] - hFX heavy chain catalytic domain + light chain (residues 84-179)<br /> | **[[1c5m]] - hFX heavy chain catalytic domain + light chain (residues 84-179)<br /> | ||
**[[1whe]], [[1whf]] – bFX GLA + EGF-like domains – bovine – NMR<br /> | **[[1whe]], [[1whf]] – bFX GLA + EGF-like domains – bovine – NMR<br /> | ||
**[[ | **[[1apo]], [[1ccf]] - bFX EGF-like domain – NMR<br /> | ||
*Factor Xa complex with inhibitor | *Factor Xa complex with inhibitor | ||
**[[ | **[[1v3x]], [[1wu1]], [[2d1j]], [[2ei6]], [[2ei7]], [[2ei8]], [[2p93]], [[2p94]], [[2p95]] – hFX heavy chain residues 16-243 + light chain EGF-like domain + inhibitor<br /> | ||
**[[1fax]], [[1fjs]], [[1g2l]], [[1g2m]], [[1ioe]], [[1iqe]], [[1iqf]], [[1iqg]], [[1iqh]], [[1iqi]], [[1iqj]], [[1iqk]], [[1iql]], [[1iqm]], [[1iqn]], [[1mq5]], [[1mq6]], [[1xka]], [[1xkb]], [[1z6e]], [[2bq6]], [[2bq7]], [[2bqw]], [[2bmg]], [[2bok]], [[2fzz]], [[2g00]], [[2jkh]], [[2p16]], [[2p3t]], [[2p3u]], [[2phb]], [[2pr3]], [[2q1j]], [[2ra0]], [[2vh0]], [[2vh6]], [[2vvc]], [[2vvu]], [[2vvv]], [[2vwl]], [[2vwm]], [[2vwn]], [[2vwo]], [[2w3i]], [[2w3k]], [[2w26]], [[2wyg]], [[2wyj]], [[2xbv]], [[2xbw]], [[2xbx]], [[2xby]], [[2xc0]], [[2xc4]], [[2xc5]], [[2y5f]], [[2y5g]], [[2y5h]], [[2y7x]], [[2y7z]], [[2y80]], [[2y81]], [[2y82]], [[3cs7]], [[3cen]], [[3ens]], [[3ffg]], [[3hpt]], [[3iit]], [[3k9x]], [[3kl6]], [[3kqb]], [[3kqc]], [[3kqd]], [[3kqe]], [[3liw]], [[3m36]], [[3m37]], [[3q3k]], [[3tk5]], [[3tk6]], [[4a7i]], [[4y6d]], [[4y71]], [[4y76]], [[4y79]], [[4y7a]], [[4y7b]] - hFX heavy chain catalytic domain + light chain EGF-like domain + inhibitor<br /> | |||
**[[ | |||
**[[2boh]] - hFX heavy chain catalytic domain (mutant) + light chain EGF-like domain (mutant) + inhibitor<br /> | **[[2boh]] - hFX heavy chain catalytic domain (mutant) + light chain EGF-like domain (mutant) + inhibitor<br /> | ||
**[[ | **[[1ezq]], [[1f0r]], [[1f0s]], [[1ksn]], [[1lpg]], [[1lpk]], [[1lpz]], [[1lqd]], [[2cji]], [[2j2u]], [[2j34]], [[2j38]], [[2j4i]], [[2j94]], [[2j95]], [[2uwl]], [[2uwo]], [[2uwp]], [[4zh8]], [[4zha]], [[5k0h]] - hFX heavy chain catalytic domain 235-488 + light chain GLA and EGF-like domains 46-179 + inhibitor<br /> | ||
**[[1nfu]], [[1nfw]], [[1nfx]], [[1nfy]] - hFX heavy chain catalytic domain + light chain residues 46-240 + inhibitor<br /> | **[[1nfu]], [[1nfw]], [[1nfx]], [[1nfy]] - hFX heavy chain catalytic domain + light chain residues 46-240 + inhibitor<br /> | ||
**[[3sw2]], [[4bti]], [[4btt]], [[4btu]] - hFX heavy chain catalytic domain + light chain residues 84-179 + inhibitor<br /> | **[[3sw2]], [[4bti]], [[4btt]], [[4btu]] - hFX heavy chain catalytic domain + light chain residues 84-179 + inhibitor<br /> | ||
