5y95 | pdb_00005y95
Haddock model of mSIN3B PAH1 domain
Structural highlights
FunctionSIN3B_MOUSE Acts as a transcriptional repressor. Interacts with MXI1 to repress MYC responsive genes and antagonize MYC oncogenic activities. Interacts with MAD-MAX heterodimers by binding to MAD. The heterodimer then represses transcription by tethering SIN3B to DNA. Also forms a complex with FOXK1 which represses transcription.[1] [2] Publication Abstract from PubMedThe neuron-restrictive silencing factor NRSF/REST binds to neuron-restrictive silencing elements in neuronal genes and recruits corepressors such as mSin3 to inhibit epigenetically neuronal gene expression. Because dysregulation of NRSF/REST is related to neuropathic pain, here, we have designed compounds to target neuropathic pain based on the mSin3-binding helix structure of NRSF/REST and examined their ability to bind to mSin3 by NMR. One compound, mS-11, binds strongly to mSin3 with a binding mode similar to that of NRSF/REST. In a mouse model of neuropathic pain, mS-11 was found to ameliorate abnormal pain behavior and to reverse lost peripheral morphine analgesia. Furthermore, even in the less well epigenetically defined case of fibromyalgia, mS-11 ameliorated symptoms in a mouse model, suggesting that fibromyalgia is related to the dysfunction of NRSF/REST. Taken together, these findings show that the chemically optimized mimetic mS-11 can inhibit mSin3-NRSF/REST binding and successfully reverse lost peripheral and central morphine analgesia in mouse models of pain. A mimetic of the mSin3-binding helix of NRSF/REST ameliorates abnormal pain behavior in chronic pain models.,Ueda H, Kurita JI, Neyama H, Hirao Y, Kouji H, Mishina T, Kasai M, Nakano H, Yoshimori A, Nishimura Y Bioorg Med Chem Lett. 2017 Oct 15;27(20):4705-4709. doi:, 10.1016/j.bmcl.2017.09.006. Epub 2017 Sep 7. PMID:28927787[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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