Fig. 2: Structural basis for inhibition of the SARS-CoV-2 polymerase complex by AT-9010.
From: A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase
a Nucplot molecular analysis with RNA, AT-9010 and nsp12. b Close up of RdRp catalytic site following AT-9010 incorporation. c Close up of RdRp catalytic site following remdesivir incorporation (PDB 7BV2). Both structures in panel b and c are in the same orientation, superimposed by least squares fit method (shown in circle). One AT-9010 5’-monophosphate (AT-9010-MP) is incorporated into the primer RNA strand, and terminates RNA elongation. The second AT-9010 molecule, coordinated by one ion, occupies the NTP-binding site in comparison, remdesivir is terminally incorporated, and untranslocated. Superimposition shows the incoming (−1) AT-9010 ribose group is shifted with the phosphates in a post-incorporation position. Ribbons are depicted as follows: nsp12, blue; nsp7, pink; nsp81 and nsp82, yellow and cyan, respectively; RNA, green sticks; AT-9010, magenta sticks. d Ligplot 2D analysis of the contacts of AT-9010 molecule with nsp12, and incorporated AT-9010-MP.
