One set of polymerase contacts, between the "thumb" domain of one polymerase and the back of the "palm" domain of another, has been previously defined.
The catalytic cycle leading to nucleotide insertion comprises several steps including a large structural rearrangement in the form of a movement of the finger domain towards the thumb domain, i.e. the transition from the open to the closed form.
Each of the inhibitors binds to NS5B non-competitively to a common binding site in the "thumb" domain that is ∼35 Å from the polymerase active site located in the "palm" domain.
Some of the newly synthesized compounds showed an IC50 ranging from 11 to 23 μM, and molecular modeling and biochemical studies suggested that the thumb domain could be the target site for this new class of NS5B inhibitors.
Thumb domain definitions were therefore based on position with respect to the palm.
Structural position of the thumb domain was conserved with respect to the palm (fig 3b, wheat), although its sequential placement varied (fig 3c, wheat).
Since the thumb domain is linked with the transmembrane domain, movement of the thumb domain causes reorientation of the transmembrane domain and modifies channel gating (see supplementary information: http://www.nature.com/nature/journal/v449/n7160/extref/nature06163-s2.htm in Ref. [5]).
The following pH-sensing mechanism wherein Asp346 plays a key role has been proposed: protonation/deprotonation of Asp346 of the thumb domain could alter the interaction with its pair partner Glu239 on the finger domain, resulting in the translocation of the thumb domain.
This β-sheet connects to both transmembrane helices and also to the thumb domain, which is composed of three helices and was suggested to play a role in the transduction of conformational changes in ASIC1 [9].
(D ) Polar contacts at the interface between Pol α's thumb domain and the RNA primer.
The ribophosphate portion of nucleotides that interact with the thumb domain is shaded gray.
