Activin receptor

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Human Acvr1 kinase domain complex with inhibitor, ethylene glycol and citrate (PDB code 4bgg)

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Function

Activin receptors (Acvr) are integral to the activin and myostatin signalling pathway. Binding of activin to the Acvr on muscle cell membrane leads to enhanced muscle protein breakdown and debilitating loss of muscle mass and functional capacity^[1].

Acvr1 is involved in bone, heart, cartilage, nervous and reproductive system development and regulation^[2].

Disease

A mutation in Acvr1 exists in individuals with the rare developmental disorder fibrodysplasia ossificans progressiva^[3].

Relevance

Increased activin/Acvr2 signalling links aging and heart failure pathobiology and that targeted inhibition of this catabolic pathway may form a therapeutic strategy for multiple forms of hear failure^[4].

Structural highlights

3D structure of the kinase domain of Acvr1 complex with inhibitor shows the inhibitor forming various interactions with the protein including a hydrogen bonds to His residues and a water bridged hydrogen bond to the catalytic lysine^[5]. Water molecule is shown as red sphere.

↑ Han HQ, Zhou X, Mitch WE, Goldberg AL. Myostatin/activin pathway antagonism: molecular basis and therapeutic potential. Int J Biochem Cell Biol. 2013 Oct;45(10):2333-47. doi:, 10.1016/j.biocel.2013.05.019. Epub 2013 May 28. PMID:23721881 doi:https://dx.doi.org/10.1016/j.biocel.2013.05.019
↑ Valer JA, Sánchez-de-Diego C, Pimenta-Lopes C, Rosa JL, Ventura F. ACVR1 Function in Health and Disease. Cells. 2019 Oct 31;8(11):1366. PMID:31683698 doi:10.3390/cells8111366
↑ Williams E, Bullock AN. Structural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2. Bone. 2017 Sep 12. pii: S8756-3282(17)30340-X. doi: 10.1016/j.bone.2017.09.004. PMID:28918311 doi:https://dx.doi.org/10.1016/j.bone.2017.09.004
↑ Roh JD, Hobson R, Chaudhari V, Quintero P, Yeri A, Benson M, Xiao C, Zlotoff D, Bezzerides V, Houstis N, Platt C, Damilano F, Lindman BR, Elmariah S, Biersmith M, Lee SJ, Seidman CE, Seidman JG, Gerszten RE, Lach-Trifilieff E, Glass DJ, Rosenzweig A. Activin type II receptor signaling in cardiac aging and heart failure. Sci Transl Med. 2019 Mar 6;11(482). pii: 11/482/eaau8680. doi:, 10.1126/scitranslmed.aau8680. PMID:30842316 doi:https://dx.doi.org/10.1126/scitranslmed.aau8680
↑ Mohedas AH, Wang Y, Sanvitale CE, Canning P, Choi S, Xing X, Bullock AN, Cuny GD, Yu PB. Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants. J Med Chem. 2014 Oct 9;57(19):7900-15. doi: 10.1021/jm501177w. Epub 2014 Sep 4. PMID:25101911 doi:https://dx.doi.org/10.1021/jm501177w

3D structures of activin receptor

Updated on 21-May-2024

References

Proteopedia Page Contributors and Editors (what is this?)

Michal Harel, Alexander Berchansky

[1] Han HQ, Zhou X, Mitch WE, Goldberg AL. Myostatin/activin pathway antagonism: molecular basis and therapeutic potential. Int J Biochem Cell Biol. 2013 Oct;45(10):2333-47. doi:, 10.1016/j.biocel.2013.05.019. Epub 2013 May 28. PMID:23721881 doi:https://dx.doi.org/10.1016/j.biocel.2013.05.019

[2] Valer JA, Sánchez-de-Diego C, Pimenta-Lopes C, Rosa JL, Ventura F. ACVR1 Function in Health and Disease. Cells. 2019 Oct 31;8(11):1366. PMID:31683698 doi:10.3390/cells8111366

[3] Williams E, Bullock AN. Structural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2. Bone. 2017 Sep 12. pii: S8756-3282(17)30340-X. doi: 10.1016/j.bone.2017.09.004. PMID:28918311 doi:https://dx.doi.org/10.1016/j.bone.2017.09.004

[4] Roh JD, Hobson R, Chaudhari V, Quintero P, Yeri A, Benson M, Xiao C, Zlotoff D, Bezzerides V, Houstis N, Platt C, Damilano F, Lindman BR, Elmariah S, Biersmith M, Lee SJ, Seidman CE, Seidman JG, Gerszten RE, Lach-Trifilieff E, Glass DJ, Rosenzweig A. Activin type II receptor signaling in cardiac aging and heart failure. Sci Transl Med. 2019 Mar 6;11(482). pii: 11/482/eaau8680. doi:, 10.1126/scitranslmed.aau8680. PMID:30842316 doi:https://dx.doi.org/10.1126/scitranslmed.aau8680

[5] Mohedas AH, Wang Y, Sanvitale CE, Canning P, Choi S, Xing X, Bullock AN, Cuny GD, Yu PB. Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants. J Med Chem. 2014 Oct 9;57(19):7900-15. doi: 10.1021/jm501177w. Epub 2014 Sep 4. PMID:25101911 doi:https://dx.doi.org/10.1021/jm501177w

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Activin receptor

Contents

Function

Disease

Relevance

Structural highlights

3D structures of activin receptor

References

Proteopedia Page Contributors and Editors (what is this?)

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