I thought I commented from your e mail. Macular degen interferes with Substack print size
I’m impressed with the thoroughness of all the changes. Change in medical knowledge is so fast understanding dufucukt. Your good humir n writing is matched with the colorful drawings. Thanks again for stimulating and teaching
Statins are the most prescribed class of drugs and inhibit a key enzyme in the cholesterol biosynthesis pathway. Many patients have reported mild to severe muscle related symptoms and a subset are at risk for rhabdomyolysis. Sequence variants in RyR1, the skeletal muscle Ryanodine Receptor, correlate with intolerance to statins, but whether RyR1 can bind statins directly has remained unclear. Here we report cryo-EM structures of RyR1 in the absence and presence of atorvastatin, firmly establishing RyR1 as an unintended off-target. Our results show an unusual binding mode whereby three atorvastatin molecules bind together in a cleft formed by the pseudo-voltage sensing domain, making extensive interactions with each other and with RyR1. Atorvastatin activates RyR1 in a sequential way, whereby one statin per subunit can bind to the transmembrane region of a closed RyR1, with small structural perturbations that prime the channel for opening. Binding of two additional statins per subunit is associated with a widening of the pseudo-voltage sensing domain that triggers opening of the pore. Comparison with atorvastatin binding to HMG-CoA reductase, its intended target, offers clues on how to modify the statin to reduce RyR1 binding, while leaving binding to HMG-CoA reductase unperturbed.
Now I'm looking for a cholesterol-lowering agent that does NOT use this mechanism!
Could you write an article about the flip-side of auto-immunity - treating cancer (particularly blood cancers) with immunotherapy?
I have written on this previously: https://erictopol.substack.com/p/unleashing-our-immune-response-to
and will return to it again. Thanks
Great news! Especially since I just got positive bloodwork for SLE in process of concerning lung scan. Fingers crossed.
I thought I commented from your e mail. Macular degen interferes with Substack print size
I’m impressed with the thoroughness of all the changes. Change in medical knowledge is so fast understanding dufucukt. Your good humir n writing is matched with the colorful drawings. Thanks again for stimulating and teaching
I have a personal interest in fibromyalgia syndromes that sometimes accompany statin therapy. Is anybody doing any good research in that area?
I haven't seen it. If you come across anything worthwhile let me know.
I came across an interesting article at https://www.nature.com/articles/s41467-025-66522-0. Abstract follows:
Statins are the most prescribed class of drugs and inhibit a key enzyme in the cholesterol biosynthesis pathway. Many patients have reported mild to severe muscle related symptoms and a subset are at risk for rhabdomyolysis. Sequence variants in RyR1, the skeletal muscle Ryanodine Receptor, correlate with intolerance to statins, but whether RyR1 can bind statins directly has remained unclear. Here we report cryo-EM structures of RyR1 in the absence and presence of atorvastatin, firmly establishing RyR1 as an unintended off-target. Our results show an unusual binding mode whereby three atorvastatin molecules bind together in a cleft formed by the pseudo-voltage sensing domain, making extensive interactions with each other and with RyR1. Atorvastatin activates RyR1 in a sequential way, whereby one statin per subunit can bind to the transmembrane region of a closed RyR1, with small structural perturbations that prime the channel for opening. Binding of two additional statins per subunit is associated with a widening of the pseudo-voltage sensing domain that triggers opening of the pore. Comparison with atorvastatin binding to HMG-CoA reductase, its intended target, offers clues on how to modify the statin to reduce RyR1 binding, while leaving binding to HMG-CoA reductase unperturbed.
Now I'm looking for a cholesterol-lowering agent that does NOT use this mechanism!