5OXG
Crystal structure of the ACVR1 (ALK2) kinase in complex with LDN-212854
Summary for 5OXG
| Entry DOI | 10.2210/pdb5oxg/pdb |
| Descriptor | Activin receptor type-1, 5-[6-(4-piperazin-1-ylphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline, CALCIUM ION, ... (5 entities in total) |
| Functional Keywords | kinase, alk2, receptor, bmp, structural genomics, structural genomics consortium, sgc, signaling protein |
| Biological source | Homo sapiens (Human) |
| Cellular location | Membrane; Single-pass type I membrane protein: Q04771 |
| Total number of polymer chains | 4 |
| Total formula weight | 140079.00 |
| Authors | Williams, E.P.,Sorrell, F.J.,Kopec, J.,Nowak, R.P.,Kupinska, K.,von Delft, F.,Burgess-Brown, N.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Bullock, A.N.,Structural Genomics Consortium (SGC) (deposition date: 2017-09-06, release date: 2017-09-20, Last modification date: 2024-10-23) |
| Primary citation | Williams, E.,Bullock, A.N. Structural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2. Bone, 109:251-258, 2018 Cited by PubMed Abstract: Individuals with the rare developmental disorder fibrodysplasia ossificans progressiva (FOP) experience disabling heterotopic ossification caused by a gain of function mutation in the intracellular region of the BMP type I receptor kinase ALK2, encoded by the gene ACVR1. Small molecule BMP type I receptor inhibitors that block this ossification in FOP mouse models have been derived from the pyrazolo[1,5-a]pyrimidine scaffold of dorsomorphin. While the first derivative LDN-193189 exhibited pan inhibition of BMP receptors, the more recent compound LDN-212854 has shown increased selectivity for ALK2. Here we solved the crystal structure of ALK2 in complex with LDN-212854 to define how its binding interactions compare to previously reported BMP and TGFβ receptor inhibitors. LDN-212854 bound to the kinase hinge region as a typical type I ATP-competitive inhibitor with a single hydrogen bond to ALK2 His286. Specificity arising from the 5-quinoline moiety was associated with a distinct pattern of water-mediated hydrogen bonds involving Lys235 and Glu248 in the inactive conformation favoured by ALK2. The structure of this complex provides a template for the design of future ALK2 inhibitors under development for the treatment of FOP and other related conditions of heterotopic ossification. PubMed: 28918311DOI: 10.1016/j.bone.2017.09.004 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.13 Å) |
Structure validation
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