Sandbox Mati

Symmetry in the Bcl-Xl interfaceSymmetry in the Bcl-Xl interface

<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 Bcl-2 family. This family consists of pro-apoptotic and 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. 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. Interestingly the interface of Bcl-Xl is almost symmetric. There are Arg 100 and Arg 139. Glu96 and Glu129. Two which include Phe191 Val141 and Ala93 for one, and the other patch includes Phe146 Val126 and Leu108. A look at the 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.