Discrimination of xenobiotics from endogenous molecules may be realized by access pathways to the binding pockets, acting as filters.

<p>(A) Based on visual examination of our simulations, two putative ligand entry pores (indicated with arrows) can be identified in the conformations of the AhR PAS B domain. Both of these regions are involved in Hsp90 binding (purple segments) suggesting that Hsp90 can directly influence the accessibility of the pores and potentially participate in ligand selection (cyan segment indicates XAP2 binding residues.) (B, C) A role of access pathways (indicated on the protein structures by blue arrows) in ligand selection has been described for nuclear receptors (B: PXR, PDBID:3R8D) and also for CYPs (C: bacterial CYP101D2, PDBID:3NV6). (D) Similarly, a substrate selective access pathway from the cytoplasmic leaflet of the membrane to the low affinity binding pocket of ABC multidrug transporters localized in the outer membrane leaflet may play a role in xenobiotics recognition (<i>T</i>. <i>maritima</i> TM287/288, PDBID:4Q4J). Blue arrows: ligand/substrate entry pathway; blue circle: location of the ligand binding pocket inside the structure.