Fig. 4: The tail anchors of PUMA and BCL-xL allosterically regulate the BH3-in-groove interface of the PUMABH3 domain within the hydrophobic groove of BCL-xL. | Nature Communications

Fig. 4: The tail anchors of PUMA and BCL-xL allosterically regulate the BH3-in-groove interface of the PUMABH3 domain within the hydrophobic groove of BCL-xL.

From: Allosteric regulation of BH3-in-groove interactions by tail anchors of BCL-xL complexes limits BH3 mimetic antagonism

Fig. 4

a PUMABH3/BCL-xL (upper panels) and dNPUMA/BCL-xL (bottom panels) complexes structures: representative structures (t = 1000 ns) are colored according to the average per-residue energy contributions, calculated using MM/GBSA from their molecular dynamic trajectories. Only residues with significant binding energy contributions (below −1.5 kcal/mol or above 1.5 kcal/mol) are displayed and annotated according to the color index. Specific residues within the BH3-in-groove of BCL-xL interacting with PUMABH3 or dNPUMA are annotated in bold with a thick arrow (middle and right panels). The underlying numerical values are given in Supplementary Table 3. The C-terminal domains are omitted at the bottom for better readability. b Dose-response antagonism by A-1331852 of YBCL-xL wt, E96A, F105A, and E129A variants complexed with either RPUMA or RPUMABH3 in MCF-7 cells. Note that for ease of comparison, the data for the response of the RPUMA/YBCL-xL and RPUMABH3/YBCL-xL complex shown in Fig. 1b have been reproduced. The representation is as described in Fig. 1b. c dNPUMA/BCL-xL E96A complex structure: average per-residue energy contributions, calculated using MM/GBSA from the 1000 ns trajectory, are projected onto the structure of dNPUMA/BCL-xL. Only residues with significant binding energy contributions (below −1.5 kcal/mol or above 1.5 kcal/mol) are displayed and annotated according to the color index. The underlying numerical values are given in Supplementary Table 3. Only residues with significant binding energy contributions (below −1.5 kcal/mol or above 1.5 kcal/mol) are displayed and annotated according to the color index. Specific residues within the BH3-in-groove of BCL-xL interacting with PUMABH3 or dNPUMA are annotated in bold with a thick arrow (middle and right panels). The underlying numerical values are given in Supplementary Table 3. The C-terminal domains are omitted at the bottom for better readability.

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