Sandbox Reserved 429
From Proteopedia
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<scene name='Sandbox_Reserved_429/Alec_alphas/1'>alpha helices</scene> | <scene name='Sandbox_Reserved_429/Alec_alphas/1'>alpha helices</scene> | ||
| - | + | 1. Basic info (size, ligand name) | |
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| - | + | 2. Origin (Zebrafish?) | |
| - | + | 3. Relation to disease (Metastatic Prostate cancer, kidney disease) | |
| - | + | 4. Pharmaceutical Applications | |
===Overall Structure=== | ===Overall Structure=== | ||
| - | <Structure load='1m4u' size='200' frame='true' align=' | + | <Structure load='1m4u' size='200' frame='true' align='center' caption='Insert caption here' scene='Insert optional scene name here' /> |
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| - | BMP-7 has a variety of structural characteristics. First and foremost are the two distinct domains which form the dimer. These are AC1 an AC2. They can be seen in red (AC1) and green(AC2) (<scene name='Sandbox_Reserved_429/Dimer/1'>TextToBeDisplayed</scene>). Notice how they are interacting but are not bound at the interface. | ||
| - | + | Draft | |
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| - | + | BMP-7 has a variety of structural characteristics. First and foremost are the two different monomers which make up the BMP-7 dimer. They can be seen in red and green to our right (<scene name='Sandbox_Reserved_429/Dimer/1'>The Dimer is composed of two non-identical structures</scene>). | |
| + | The secondary structures in BMP-7 are vital to the proteins function (specifically the binding). The alpha helicies and beta sheets can be seen in red and blue respectively in the green screen to the right(<scene name='Sandbox_Reserved_429/Secondary_structure_highlight/1'>Secondary Structures Highlighted</scene>). The anti parallel beta sheets in the second sequence (the smaller domain) are vital for the binding interactions of the molecule. | ||
| + | Chain A is the most functionally important to the molecule. It contains the regions for cytokine binding, protein complex binding, and protein homodimerization [1]. These functions are discussed in the following binding section. | ||
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| - | 6. Primary Structure? Secondary? Tertiary? | ||
===Binding Interactions=== | ===Binding Interactions=== | ||
Revision as of 16:55, 16 April 2012
| This Sandbox is Reserved from January 19, 2016, through August 31, 2016 for use for Proteopedia Team Projects by the class Chemistry 423 Biochemistry for Chemists taught by Lynmarie K Thompson at University of Massachusetts Amherst, USA. This reservation includes Sandbox Reserved 425 through Sandbox Reserved 439. |
Contents |
YourMacromolecule
Introduction
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1. Basic info (size, ligand name)
2. Origin (Zebrafish?)
3. Relation to disease (Metastatic Prostate cancer, kidney disease)
4. Pharmaceutical Applications
Overall Structure
|
Draft
BMP-7 has a variety of structural characteristics. First and foremost are the two different monomers which make up the BMP-7 dimer. They can be seen in red and green to our right (). The secondary structures in BMP-7 are vital to the proteins function (specifically the binding). The alpha helicies and beta sheets can be seen in red and blue respectively in the green screen to the right(). The anti parallel beta sheets in the second sequence (the smaller domain) are vital for the binding interactions of the molecule. Chain A is the most functionally important to the molecule. It contains the regions for cytokine binding, protein complex binding, and protein homodimerization [1]. These functions are discussed in the following binding section.
Binding Interactions
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Draft
BMP-7 uses two pairs of antiparallel referred as Finger 1 and Finger 2 for binding activities. The curvature of the fingers creates a site in which the α3 of the other subunit binds to stabilize the
. Free BMP-7 shows in the "wrist " and "knuckles" areas upon complexing with receptors and antagonist proteins. [A]
by BMP-7 occurs by the binding of the protein to high affinity type II receptor (at the knuckles epitope) follow by the recruitment of the low affinity type I receptor (at the "wrist " epitope). The binding causes the trans-phosphorylation of the Type I receptor at a a glycine- and serine- rich region (GS-Box) by the type II receptor kinase. Afterwards the type I receptor Ser/Thr-kinase activates leading to intracellular signaling. [C]
Bone morphogenetic proteins (BMPs)are regulated by the binding of three classes of antagonist inhibitory proteins: Noggin; the DAN family; and verterbrate Chordin and Drosophila SOG. Noggin is a homologous BMP-specific anatagonist protein found to regulate the dorsal structures in ventralized Xenopus embryos. The structure of the C-terminal half of the Noggin resembles the BMPs in that it have two pairs of antiparallel β-strands extending out from a core containing disulphides bonds. In contrast to BMP-7, binding of the monomer consists of interaction between the α4 of each monomer. When noggin binds to BMP-7, the tip of finger 1 and 2 in BMP-7 curls around the N-terminal segment of the noggin. [A]
BMP ligands have two prominent hydrophobic patches for receptor binding interfaces: convex type II and concave type I. Superposition of the noggin-BMP-7 structure show the masking of both pairs of binding epitopes. The obstruction of the type I receptor-binding occurs due to hydrophobic interactions. The hydrophobic ring of Pro 35 of the noggin inserts into the hydrophobic pocket on BMP-7 formed by Trp 52, Trp 55, Val 87, Tyr 128, and Met 131. In contrast, the type II receptor-binding is obstructed by the C-terminal half of the clip segment by the distal tip of finger 1 and by finger 2. [A]
In summary, the binding of noggin to BMP-7 consists of a hydrophobic side chain from the backbone insetred into the hydrophobic pocket of BMP followed by complementary interactions between two curved hydrophobic surfaces.
Follistatin is a proposed BMP antagonist which is present in embryonic muscle cells. The BMP antagonist enhances the BMP-7 action for muscle grwoth but it prevents the induction of apoptosis and muscle loss. The antagonist protein interacts directly with BMP but does not prevent the ligan from binding to its receptors resulting in a trimeric complex. [B]
Additional Features
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1. Mutations in NOG
a.Substitutions of six positions :Pro35Arg, Cys184Tyr, Gly189Cys, Ile220Asn, Tyr222Cys/ Tyr222Asn, Pro223Leu affect folding stability
b. Pro35Arg - decreased affinity, diminished inhibition of chondrogenesis
c. Pro35Ser- similar
2. BMP regulators evolution -BMP signalling pathway, gene duplication ligand receptor - structural homology between agonists and antagonists
Credits
Introduction - Alec
Overall Structure - William
Drug Binding Site - Felix
Additional Features - Paula
References
[A]Groppe J, Greenwald J, Wiater E, Rodriguez-Leon J, Economides AN, Kwiatkowski W, Affolter M, Vale WW, Belmonte JC, Choe S. Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature. 2002 Dec 12;420(6916):636-42. PMID:12478285 doi:10.1038/nature01245
[B]Floriani, C., and F. Calderazzo. "Oxygen Adducts of Schiff's Base Complexes of Cobalt Prepared in Solution." Journal of the Chemical Society A: Inorganic, Physical, Theoretical (1969): 946-53. Print.
[C]Sebald, Walter, and Thomas D. Mueller. "The Interaction of BMP-7 and ActRII Implicates a New Mode of Receptor Assembly." Trends in biochemical sciences 28.10 (2003): 518-21. Print.
