3my0 | pdb_00003my0
Crystal structure of the ACVRL1 (ALK1) kinase domain bound to LDN-193189
Structural highlights
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Disease[ACVL1_HUMAN] Defects in ACVRL1 are the cause of hereditary hemorrhagic telangiectasia type 2 (HHT2) [MIM:600376]; also known as Osler-Rendu-Weber syndrome 2 (ORW2). HHT2 is an autosomal dominant multisystemic vascular dysplasia, characterized by recurrent epistaxis, muco-cutaneous telangiectases, gastro-intestinal hemorrhage, and pulmonary, cerebral and hepatic arteriovenous malformations; all secondary manifestations of the underlying vascular dysplasia.[1] [2] [3] [4] [5] [6] [7] [8] [9] Function[ACVL1_HUMAN] Type I receptor for TGF-beta family ligands BMP9/GDF2 and BMP10 and important regulator of normal blood vessel development. On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. May bind activin as well.[10] [11] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedActivin receptor-like kinase 1 (ALK1, encoded by the gene ACVRL1) is a type I BMP/TGF-beta receptor that mediates signalling in endothelial cells via phosphorylation of SMAD1/5/8. During angiogenesis, sprouting endothelial cells specialise into tip cells and stalk cells. ALK1 synergises with Notch in stalk cells to induce expression of the Notch targets HEY1 and HEY2 and thereby represses tip cell formation and angiogenic sprouting. The ALK1-Fc soluble protein fusion has entered clinic trials as a therapeutic strategy to sequester the high-affinity extracellular ligand BMP9. Here, we determined the crystal structure of the ALK1 intracellular kinase domain and explored the effects of a small molecule kinase inhibitor K02288 on angiogenesis. K02288 inhibited BMP9-induced phosphorylation of SMAD1/5/8 in human umbilical vein endothelial cells to reduce both the SMAD and the Notch-dependent transcriptional responses. In endothelial sprouting assays, K02288 treatment induced a hypersprouting phenotype reminiscent of Notch inhibition. Furthermore, K02288 caused dysfunctional vessel formation in a chick chorioallantoic membrane assay of angiogenesis. Such activity may be advantageous for small molecule inhibitors currently in preclinical development for specific BMP gain of function conditions, including diffuse intrinsic pontine glioma and fibrodysplasia ossificans progressiva, as well as more generally for other applications in tumour biology. A small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis.,Kerr G, Sheldon H, Chaikuad A, Alfano I, von Delft F, Bullock AN, Harris AL Angiogenesis. 2015 Apr;18(2):209-17. doi: 10.1007/s10456-014-9457-y. Epub 2015, Jan 4. PMID:25557927[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Proteopedia Page Contributors and Editors (what is this?)
- Human
- Receptor protein serine/threonine kinase
- Alfano, I
- Arrowsmith, C H
- Bountra, C
- Bullock, A
- Carpenter, C P
- Chaikuad, A
- Cooper, C
- Daga, N
- Delft, F von
- Edwards, A M
- Fedorov, O
- Gileadi, O
- Knapp, S
- Krojer, T
- Mahajan, P
- Muniz, J R.C
- Petrie, K
- Pike, A C.W
- Structural genomic
- Sanvitale, C
- Savitsky, P
- Sethi, R
- Ugochukwu, E
- Vollmar, M
- Weigelt, J
- Protein kinase
- Serine/threonine-protein kinase receptor
- Sgc
- Transferase
