Pua Khian Hong, Stiles Dylan T, Sowa Mathew E, Verdine Gregory L
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Warp Drive Bio, Cambridge, MA 02139, USA.
Warp Drive Bio, Cambridge, MA 02139, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Cell Rep. 2017 Jan 10;18(2):432-442. doi: 10.1016/j.celrep.2016.12.030.
Natural products have demonstrated utility in the clinic and can also act as probes to understand complex cellular pathways. Sanglifehrin A (SFA) is a mixed polyketide and non-ribosomal peptide synthase natural product with sub-nano-molar affinity for its receptor cyclophilin A (PPIA). It has been shown to behave in vitro as an immune suppressant. Here, we identify inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) as an intracellular target of the PPIA-SFA binary complex. The formation of this ternary complex does not inhibit the enzymatic activity of IMPDH2. Rather, ternary complex formation modulates cell growth through interaction with the cystathionine-β-synthase (CBS) domain of IMPDH2. We further demonstrate that the SFA complex is highly isoform selective for IMPDH2 (versus IMPDH1). This work reveals a role for the CBS domains of IMPDH2 in cellular proliferation, suggesting a more complex role than previously suspected for IMPDH2 in T cell activation and proliferation.
天然产物已在临床中显示出效用，并且还可作为理解复杂细胞通路的探针。桑吉霉素A（SFA）是一种混合聚酮化合物和非核糖体肽合成酶天然产物，对其受体亲环素A（PPIA）具有亚纳摩尔亲和力。体外实验表明它具有免疫抑制作用。在此，我们确定肌苷-5'-单磷酸脱氢酶2（IMPDH2）是PPIA-SFA二元复合物的细胞内靶点。这种三元复合物的形成并不抑制IMPDH2的酶活性。相反，三元复合物的形成通过与IMPDH2的胱硫醚-β-合酶（CBS）结构域相互作用来调节细胞生长。我们进一步证明，SFA复合物对IMPDH2（相对于IMPDH1）具有高度的异构体选择性。这项工作揭示了IMPDH2的CBS结构域在细胞增殖中的作用，表明IMPDH2在T细胞活化和增殖中的作用比以前怀疑的更为复杂。
