Structural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2
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 re...
| Main Authors: | , |
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| Format: | Journal article |
| Language: | English |
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Elsevier
2017
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| _version_ | 1797052581003919360 |
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| author | Williams, E Bullock, A |
| author_facet | Williams, E Bullock, A |
| author_sort | Williams, E |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T18:33:32Z |
| format | Journal article |
| id | oxford-uuid:0a77cc92-4c73-45e9-a2bf-68f21ff8285b |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:33:32Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:0a77cc92-4c73-45e9-a2bf-68f21ff8285b2022-03-26T09:24:03ZStructural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0a77cc92-4c73-45e9-a2bf-68f21ff8285bEnglishSymplectic Elements at OxfordElsevier2017Williams, EBullock, AIndividuals 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. |
| spellingShingle | Williams, E Bullock, A Structural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2 |
| title | Structural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2 |
| title_full | Structural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2 |
| title_fullStr | Structural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2 |
| title_full_unstemmed | Structural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2 |
| title_short | Structural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2 |
| title_sort | structural basis for the potent and selective binding of ldn 212854 to the bmp receptor kinase alk2 |
| work_keys_str_mv | AT williamse structuralbasisforthepotentandselectivebindingofldn212854tothebmpreceptorkinasealk2 AT bullocka structuralbasisforthepotentandselectivebindingofldn212854tothebmpreceptorkinasealk2 |