Structural studies identify angiotensin II receptor blocker-like compounds as branched-chain ketoacid dehydrogenase kinase inhibitors

Combining structural and coevolution information to unveil allosteric sites

“…Notably, a recently published work reports putative allosteric inhibitors binding to this pocket, supporting our predictions. 65 Other known functionally relevant sites in p38-α, such as the noncanonical site and the D-groove, are not placed in the R 33% , being ranked at the 6th and 8th position, respectively ( Fig. 5 ).…”

The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis

“…Of course, it may be that other off-target effects of BT2 in addition to chemical uncoupling contribute to observed in vitro and in vivo phenotypes. For example, recent reports highlight shared pharmacology between angiotensin II type 1 receptor blockers and BT2 ( 68 ). Encouragingly, regulation of the renin–angiotensin system may mechanistically explain the effect of BT2 on blood pressure despite Bckdk ablation ( 27 ), a result unlikely to be directly caused by mitochondrial uncoupling.…”

Computational structural genomics and clinical evidence suggest BCKDK gain‐of‐function may cause a potentially asymptomatic maple syrup urine disease phenotype

“…BCKDK belongs to the histidine kinase family 4 and is made of the active site‐containing catalytic domain (K domain) and the four‐helix bundle regulatory domain (B‐domain) that contains the lipoyl‐binding site and the allosteric inhibitor (feed‐forward inhibition by α‐ketoisocaproic acid) binding site 16,17 . Several crystal structures of the BCKDK catalytic domain have been determined in rats, which share a 95.6% sequence identity with the human protein 18,19 . We used the AlphaFold model structure in which all differential sequences in rats (six residues) have been replaced with the human sequences and the missing regions in the crystal structures, such as the N‐terminal extension and the flexible loop (1–67 and 337–361 in the human sequence), have been completed 20 .…”

“… 16 , 17 Several crystal structures of the BCKDK catalytic domain have been determined in rats, which share a 95.6% sequence identity with the human protein. 18 , 19 We used the AlphaFold model structure in which all differential sequences in rats (six residues) have been replaced with the human sequences and the missing regions in the crystal structures, such as the N‐terminal extension and the flexible loop (1–67 and 337–361 in the human sequence), have been completed. 20 We used two different structures—the catalytic domain only (56–412) and the full‐length protein (1–412)—for our analysis; both structures contain the cofactor ATP and the bound K + and Mg ++ ions in the active site.…”