دورية أكاديمية
أعرض في EDS

Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva.

التفاصيل البيبلوغرافية
العنوان: Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva.
المؤلفون: Chaikuad A; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, United Kingdom., Alfano I, Kerr G, Sanvitale CE, Boergermann JH, Triffitt JT, von Delft F, Knapp S, Knaus P, Bullock AN
المصدر: The Journal of biological chemistry [J Biol Chem] 2012 Oct 26; Vol. 287 (44), pp. 36990-8. Date of Electronic Publication: 2012 Sep 12.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
مواضيع طبية MeSH: Activin Receptors, Type I/*chemistry , Myositis Ossificans/*enzymology, Activin Receptors, Type I/antagonists & inhibitors ; Activin Receptors, Type I/genetics ; Activin Receptors, Type I/metabolism ; Amino Acid Motifs ; Animals ; Bone Morphogenetic Protein 4/physiology ; Catalytic Domain ; Crystallography, X-Ray ; Enzyme Activation ; Gene Expression Regulation ; Genes, Reporter ; Humans ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Luciferases, Firefly/biosynthesis ; Luciferases, Firefly/genetics ; Mice ; Models, Molecular ; Mutation, Missense ; Myositis Ossificans/genetics ; Protein Binding ; Pyrazoles/chemistry ; Pyrimidines/chemistry ; Signal Transduction ; Tacrolimus/pharmacology ; Tacrolimus Binding Protein 1A/antagonists & inhibitors ; Tacrolimus Binding Protein 1A/chemistry ; Tacrolimus Binding Protein 1A/metabolism
مستخلص: Bone morphogenetic protein (BMP) receptor kinases are tightly regulated to control development and tissue homeostasis. Mutant receptor kinase domains escape regulation leading to severely degenerative diseases and represent an important therapeutic target. Fibrodysplasia ossificans progressiva (FOP) is a rare but devastating disorder of extraskeletal bone formation. FOP-associated mutations in the BMP receptor ALK2 reduce binding of the inhibitor FKBP12 and promote leaky signaling in the absence of ligand. To establish structural mechanisms of receptor regulation and to address the effects of FOP mutation, we determined the crystal structure of the cytoplasmic domain of ALK2 in complex with the inhibitors FKBP12 and dorsomorphin. FOP mutations break critical interactions that stabilize the inactive state of the kinase, thereby facilitating structural rearrangements that diminish FKBP12 binding and promote the correct positioning of the glycine-serine-rich loop and αC helix for kinase activation. The balance of these effects accounts for the comparable activity of R206H and L196P. Kinase activation in the clinically benign mutant L196P is far weaker than R206H but yields equivalent signals due to the stronger interaction of FKBP12 with R206H. The presented ALK2 structure offers a valuable template for the further design of specific inhibitors of BMP signaling.
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معلومات مُعتمدة: United Kingdom WT_ Wellcome Trust; 092809 United Kingdom WT_ Wellcome Trust; 092809/Z/10/Z United Kingdom WT_ Wellcome Trust; Canada CAPMC CIHR
سلسلة جزيئية: PDB 3H9R
المشرفين على المادة: 0 (BMP4 protein, human)
0 (Bone Morphogenetic Protein 4)
0 (Pyrazoles)
0 (Pyrimidines)
10K52CIC1Z (dorsomorphin)
EC 1.13.12.7 (Luciferases, Firefly)
EC 2.7.11.30 (ACVR1 protein, human)
EC 2.7.11.30 (Activin Receptors, Type I)
EC 5.2.1.- (Tacrolimus Binding Protein 1A)
WM0HAQ4WNM (Tacrolimus)
تواريخ الأحداث: Date Created: 20120915 Date Completed: 20130107 Latest Revision: 20240630
رمز التحديث: 20240630
مُعرف محوري في PubMed: PMC3481300
DOI: 10.1074/jbc.M112.365932
PMID: 22977237
قاعدة البيانات: MEDLINE
الوصف
تدمد:1083-351X
DOI:10.1074/jbc.M112.365932