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| - | [[Image:Coag_cartoon.jpg | thumb |350px| Schematic representation of the coagulation response]]
| + | ==Symmetry in the Bcl-Xl interface== |
| - | ==Coagulation Factor XIa== | + | <StructureSection load='2yxj_With_Ligand_Mati_Cohen.pdb' size='500' frame='true' align='right' caption='Bcl-Xl and ABT737 from PDB-ID 2yxj' scene=''>Bcl-Xl is a member of the [http://en.wikipedia.org/wiki/Bcl-2 Bcl-2 family]. This family consists of [http://en.wikipedia.org/wiki/Apoptosis pro-apoptotic] and [http://en.wikipedia.org/wiki/Apoptosis anti-apoptotic] members. Bcl-Xl (in the image) ,an anti-apoptotic protein, binds pro-apoptotic proteins like BAK and BAD thus regularly inhibit program cell death. Many cancer cells overexpress at least one of the anti-apoptotic members of this family ,thus escaping a needed apoptosis . Therefore, these proteins are important targets for the development of new anti-cancer drugs. |
| - | ==Introduction== | + | The PDB file [[2yxj]] shows the structure of Bcl-Xl and ABT 737. ABT 737 is a potent inhibitor of Bcl-Xl (Kd = 1nM). It binds Bcl-xl in the same position as BAK does as can be seen in [[1bxl]]. |
| - | Factor XIa is unique protease derived from the activation of the coagulation zymogen, factor XI. Factor XIa partcipates in the procoagulant response via contact activation pathway. Synthesized by the liver similar to most vitamin K-dependent coagulation proteins, the zymogen, factor XI circulates in plasma as a 160 kDa disulfide-linked homodimer in complex with high molecular weight kininogen (HK)<ref>PMID:915004</ref>. Studies show that factor XI is a substrate for various plasma proteins such as factor XIIa, thrombin, meizothrombin and factor XIa (via autoactivation). Proteolysis of the Arg369-Ile370 bond generates the active enzyme factor XIa which in turn cleaves its substrate factor factor IX to produce the serine protease factor IXa.
| + | Interestingly the interface of Bcl-Xl is almost symmetric. There are <scene name='43/437742/2yxj_arg/9'>two positively charged residues</scene> Arg 100 and Arg 139. |
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| + | <scene name='43/437742/2yxj_glu/7'>two negatively charged residues</scene> Glu96 and Glu129. |
| - | ==Protein Structure==
| + | Two <scene name='43/437742/2yxj_hyd/4'>hydrophobic patches</scene> which include Phe191 Val141 and |
| - | Each dimeric subunit of factor XIa exhibit similar amino acid composition of about 607 residues constituting five main domains. The N-terminus of each subunit contains 4 apple domains (A1, A2, A3 and A4) which are characterized by approximately 90 or 91 amino acid repeats. The C-terminus contain the trypsin-like catalytic domain. Together with Prekallikrein (PK) a monomeric homolog of factor XIa, they belong to the PAN (plasminogen, apple, nematode) module family which all have a conserved N-terminal apple domain )<ref>PMID:10561497</ref>. The topology of the apple domain reveals 7 antiparallel β-sheets and an α-helix which fold into a compact structure as oppose to an extended structure found in the vitamin K-dependent serine proteases. This core PAN topology is also found in leech antiplatelet protein and hepatocyte growth factor)<ref>PMID:10561497</ref>. A single disulfide linkage connects the C- and N-terminals of the dimer whereas two disulfide bond join the heix to the 4β- and 5β-sheets. The apple domains of Factor XIa are tightly linked to each other forming a disk-like structure closed to the base of the C-terminal catalytic domain. This observation is consistent with the high surface area measurements for the side interfaces between apple domains A1 and A2 (441ÅxÅ) and between A3 and A4 (444ÅxÅ) in contrast to smaller end interfaces between A1 and A4(380ÅxÅ) and between A2 and A3(284ÅxÅ).
| + | Ala93 for one, and the other patch includes Phe146 Val126 and Leu108. A look at the <scene name='43/437742/2yxj_space_fill_color_charged/3'>Overall</scene> picture shows that there are hydrophobic patches (in gray) "above" and "below" the ligand ,negatively charged residues "above-right" and "below-left" of the ligand and positively charges on the "right" and "left" of it. |
| - | | + | This symmetry can be exploited, a symmetric molecule can bind the same interface in two different ways thus increasing the "chance" of binding which means better binding affinity. |
| - | ==Formation of the active enzyme, factor XIa via factor XI zymogen activation==
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| - | Factor XI is partially proteolyzed in vitro by thrombin and factor XIIa generating the active serine-protease, factor XIa. Similar to other chymotrypsin-like proteases, its topology consist of two β-barrels linked through a central loop. Next to the C-terminal Cys356 of the factor XI heavy chain, the polypeptide forms a 3-10 helix conformation and again turn sharply 90 degrees at Cys362 forming a disulfide bond with Cys482 within the active site region. Thrombin-catalyzed proteolysis of factor XI involves binding to Glu66, Lys83 and Gln84 of the AI domainage of (this ensures maximum proximity to the activation loop of factor XI)<ref>PMID:16699514</ref>. Binding of thrombin to one subunit of the dimer promotes cleavage of the bond between Arg369-Ile370 found in the activation loop. The activation loop (residues 366-370) undergoes the greatest conformational change as Ile370 is displaced 20Å from its position in factor XI and inserts into the activation pocket of factor XIa producing the oxyanion hole in the active site of the protease <ref>PMID:14523451</ref>.
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| - | ==Active Site Characteristics==
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| - | The <scene name='Sandbox/Active_site/1'>active site</scene>
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| - | <Structure load='3bg8' size='400' frame='true' align='right' caption='Factor XIa light chain' scene='Insert optional scene name here' /> | + | |
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| - | ==Recognition of Substrates and Cleavege Mechanism==
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| - | ==References==
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| - | <references />
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