6btq

BMP1 complexed with a hydroxamate - compound 2

spinqualitylabelsall models 6btq, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6btq is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.75Å Ligands: ACE, E8S, EDO, SCN, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease BMP1_HUMAN Defects in BMP1 are the cause of osteogenesis imperfecta 13 (OI13) [MIM:614856. An autosomal recessive form of osteogenesis imperfecta, a connective tissue disorder characterized by bone fragility, low bone mass, and recurrent fractures. OI13 is characterized by normal teeth, faint blue sclerae, severe growth deficiency, borderline osteoporosis, severe bone deformity, and recurrent fractures affecting both upper and lower limbs. Function BMP1_HUMAN Cleaves the C-terminal propeptides of procollagen I, II and III. Induces cartilage and bone formation. May participate in dorsoventral patterning during early development by cleaving chordin (CHRD). Responsible for the proteolytic activation of lysyl oxidase LOX. Publication Abstract from PubMed Bone Morphogenetic Protein 1 (BMP1) inhibition is a potential method for treating fibrosis because BMP1, a member of the zinc metalloprotease family, is required to convert pro-collagen to collagen. A novel class of reverse hydroxamate BMP1 inhibitors was discovered, and cocrystal structures with BMP1 were obtained. The observed binding mode is unique in that the small molecule occupies the nonprime side of the metalloprotease pocket providing an opportunity to build in metalloprotease selectivity. Structure-guided modification of the initial hit led to the identification of an oral in vivo tool compound with selectivity over other metalloproteases. Due to irreversible inhibition of cytochrome P450 3A4 for this chemical class, the risk of potential drug-drug interactions was managed by optimizing the series for subcutaneous injection. Reverse Hydroxamate Inhibitors of Bone Morphogenetic Protein 1.,Kallander LS, Washburn D, Hilfiker MA, Eidam HS, Lawhorn BG, Prendergast J, Fox R, Dowdell S, Manns S, Hoang T, Zhao S, Ye G, Hammond M, Holt DA, Roethke T, Hong X, Reid RA, Gampe R, Zhang H, Diaz E, Rendina AR, Quinn AM, Willette B ACS Med Chem Lett. 2018 Jul 2;9(7):736-740. doi: 10.1021/acsmedchemlett.8b00173. , eCollection 2018 Jul 12. PMID:30034610 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Bone morphogenetic protein 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA