9NRC
TMPRSS6 in complex with REGN7999 Fab and REGN8023 Fab
Summary for 9NRC
| Entry DOI | 10.2210/pdb9nrc/pdb |
| EMDB information | 49728 |
| Descriptor | Transmembrane protease serine 6, REGN7999 Fab light chain, REGN7999 Fab heavy chain, ... (8 entities in total) |
| Functional Keywords | serine protease, matriptase, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 185624.73 |
| Authors | |
| Primary citation | Lob, H.E.,Singh, N.,Mohammadi, K.,Ivanova, L.,Crowell, B.,Kim, H.J.,Kravets, L.,Das, N.M.,Ray, Y.,Kim, J.H.,Rottey, S.,Labriola-Tompkins, E.,Hassan, H.E.,Farrelly, L.,Chin, H.F.,Preda, M.,Spencer Noakes, L.,Saotome, K.,Franklin, M.,Retter, M.W.,Karayusuf, E.,Flanagan, J.J.,Olson, W.,Nannuru, K.C.,Idone, V.,Burczynski, M.E.,Harari, O.A.,Perlee, L.,Van Lancker, G.,Murphy, A.J.,Economides, A.N.,Hatsell, S.J. A TMPRSS6-inhibiting mAb improves disease in a beta-thalassemia mouse model and reduces iron in healthy humans. JCI Insight, 10:-, 2025 Cited by PubMed Abstract: β-Thalassemia is a genetic disorder arising from mutations in the β-globin gene, leading to ineffective erythropoiesis and iron overload. Ineffective erythropoiesis, a hallmark of β-thalassemia, is an important driver of iron overload, which contributes to liver fibrosis, diabetes, and cardiac disease. Iron homeostasis is regulated by the hormone hepcidin; BMP6/hemojuvelin-mediated (BMP6/HJV-mediated) signaling induces hepatic hepcidin expression via SMAD1/5, with transmembrane serine protease 6 (TMPRSS6) being a negative regulator of HJV. Individuals with loss-of-function mutations in the TMPRSS6 gene show increased circulating hepcidin and iron-refractory iron-deficiency anemia, suggesting that blocking TMPRSS6 may be a viable strategy to elevate hepcidin levels in β-thalassemia. We generated a human mAb (REGN7999) that inhibits TMPRSS6. In an Hbbth3/+ mouse model of β-thalassemia, REGN7999 treatment led to significant reductions in liver iron, reduced ineffective erythropoiesis, and showed improvements in RBC health, running distance during forced exercise, and bone density. In a phase I, doubleblind, randomized, placebo-controlled study in healthy human volunteers (NCT05481333), REGN7999 increased serum hepcidin and reduced serum iron with an acceptable tolerability profile. Our results suggest that, by both reducing iron and improving RBC function, inhibition of TMPRSS6 by REGN7999 may offer a therapy for iron overload and impaired erythropoiesis in β-thalassemia. PubMed: 40548380DOI: 10.1172/jci.insight.191813 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.29 Å) |
Structure validation
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