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| | ===Introduction=== | | ===Introduction=== |
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| - | <Structure load='1m4u' size='500' frame='true' align='right' caption='The complex formed between the antagonist Noggin and BMP-7.' scene='Bone morphogenetic protein 7 complexed with Noggin' /> | |
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| - | <scene name='Sandbox_Reserved_429/Alec_bmp_alone/1'>Bone Morphogenetic Protein 7</scene> (BMP-7) is a protein that is involved in a variety of aspects of embryonic and adult development. Some of the areas it is involved in are neural tissue induction, the formation of bones and joints in the skeletal system, and neurogenesis in the adult brain. It regulated through the binding of different antagonists, such as Noggin, forming <scene name='Sandbox_Reserved_429/Alec_noggin_complex/2'>this complex</scene> that shows the two separate components of the complex.
| + | =='''YourMacromolecule'''== |
| - | Neural induction is the process by which the undifferentiated ectoderm layer of the embryo are signaled to form neuro-ectoderm cells by the mesoderm. These differentiated cells will become neural cells. Only some of the cells are signaled to differentiate in this way, and the rest become the epidermis.
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| - | In bone formation, first a flexible membrane is formed in the embryo that develops into cartilage. As the embryo develops, signaling through proteins in the BMP family including BMP-7 causing ossification to occur, which is the process of forming bone, replacing the cartilage membranes. This can be seen in the development of the skull. BMP can also signal for cartilage to transform to bone, which is how much of the rest of the skeleton develops.
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| - | One of the most important aspects of BMP-7 is its role in neurogenesis in the adult brain. Neurogenesis is the process by which new neurons are created in the adult brain. Initially it was thought that proteins in the BMP family would inhibit neurogenesis unless deactivated by the antagonist, Noggin. But when the levels of neurogenesis were examined with the over expression and signalling of BMP, there was no inhibition of the creation of neurons. In fact further research has shown that BMP-mediated signalling is required to allow neurogenesis in adults.[i]
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| - | Because BMP’s are crucial in much of the development and upkeep of many organs and systems, there are many disease that can arise or be affected by dysfunctional BMP genes and proteins. The incorrect implementation of BMP-7 during development can result in issues with skeletal and neural development. BMP-7 can also have impacts after the initial fetal development. Research has linked a lack of BMP-7 signalling to the progression of gastrointestinal cancers, particularly colon and esophageal cancer.[ii]
| + | ===Introduction=== |
| - | | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
| - | There have also been developments in using BMP’s as therapeutics. Because the main role of BMP’s is bone formation, one of the most promising areas is in bone reformation after injury. BMP-7 and BMP-2 have been successfully adapted and used in combination with bone grafts during surgery, and have been extremely useful in spinal cervical fusion. [iii]
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| - | While these therapeutics are great developments, there is still much more potential because of the effects of BMP on the whole body. Currently, research is being conducted to understand how BMP-7 can be used in treating chronic kidney disease. And because of the ability to regulate neurogenesis, it is possible that BMP proteins can be used in the treatment or cure of neurodegenerative diseases such as Alzheimer's. [ii]
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| | ===Overall Structure=== | | ===Overall Structure=== |
| - | <Structure load='1m4u' size='500' frame='true' align='right' caption='Analysis of BMP-7 Structure' scene='Insert optional scene name here' /> | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, insert caption here' scene='Sandbox_Reserved_430/Intra-strand_phosphate/1' /> |
| - | | + | <br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br> |
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| - | BMP-7 has a variety of structural characteristics. First and foremost are the two different proteins which make up the Bone Formation complex. We can see <span style="color:green">'''BMP-7'''</span> and the <span style="color:red">'''Noggin'''</span> in the scene to the right (<scene name='Sandbox_Reserved_429/Dimer/1'>Dimer</scene>).
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| - | The secondary structures in BMP-7 are vital to the proteins function (specifically the binding). The <span style="color:red">'''alpha helicies'''</span> and <span style="color:blue">'''beta sheets'''</span> in the green screen to the right (<scene name='Sandbox_Reserved_429/Alpha_helicies_and_beta_sheets/1'>Secondary Structure</scene>). The anti parallel beta sheets in the BMP-7 portion of the complex (the smaller domain) are vital for the binding interactions of the molecule. It is these anti-parrallel sheets which bind Noggin (the aforementioned red protein). These are pointed towards in the previous depiction.
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| - | BMP-7 is the most functionally important to the molecule. It contains the regions for cytokine binding, protein complex binding, and protein homodimerization <ref>PMID: 12478285</ref>. These functions are discussed in the following binding section.
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| - | In addition to these pieces there are two important sites AC1 and AC2. The AC1 site is pictured as follows, the active site is in between the red colored faces of the beta sheets. <scene name='Sandbox_Reserved_429/Ac1_site/1'>AC1</scene>.
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| - | Lastly there is a site for a ligand to bind. The location of these anti parallel binding sheets is seen <scene name='Sandbox_Reserved_429/Ligand/1'>here</scene>.
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| | ===Binding Interactions=== | | ===Binding Interactions=== |
| | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
| | + | <br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br> |
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| - | <Structure load='1m4u' size='500' frame='true' align='right' caption='BMP-7 Complexed with noggin displayed of active binding sites' scene='Insert optional scene name here' /> | + | ===Additional Features=== |
| | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
| | + | <br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br> |
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| | + | ===Quiz Question 1=== |
| | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
| | + | <br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br> |
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| - | BMP-7 uses two pairs of antiparallel <scene name='Sandbox_Reserved_429/Free_bmp_labeled/1'>β-strands</scene> referred as <span style="color:green">'''Finger 1'''</span> and <span style="color:orangered">'''Finger 2'''</span> for binding activities. The curvature of the fingers creates a site in which the <span style="color:darkviolet">'''α3'''</span> of the other subunit binds to stabilize the
| + | ===Quiz Question 2=== |
| - | <scene name='Sandbox_Reserved_429/Unbounded_bmp7/1'>dimer</scene>. Free BMP-7 shows conformational changes in the "<span style="color:deepskyblue">'''wrist'''</span> " and "<span style="color:darkviolet">'''knuckles'''</span>" areas upon complexing with receptors and antagonist proteins.<ref>PMID: 12478285</ref> <scene name='Sandbox_Reserved_429/Knuckles_wrist_free/1'>Uncomplexed BMP-7</scene> has <span style="color:green">'''Finger 1'''</span> and <span style="color:orangered">'''Finger 2'''</span> have a flat shape, however upon <scene name='Sandbox_Reserved_429/Confirmational/2'>complexing</scene> with noggin or another BMP-7 the protein adopts an arc shape. | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
| | + | <br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br> |
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| - | <scene name='Sandbox_Reserved_429/Signaling/1'>Signaling</scene> by BMP-7 occurs by the binding of the protein to high affinity type II receptor (at the <span style="color:darkviolet">'''knuckles'''</span> epitope) follow by the recruitment of the low affinity type I receptor (at the "<span style="color:deepskyblue">'''wrist'''</span> " 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.<ref>PMID: 14559178</ref> Afterwards the type I receptor Ser/Thr-kinase activates leading to intracellular signaling.
| + | ===Credits=== |
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| | + | Introduction - name of team member |
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| - | 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 <scene name='Sandbox_Reserved_429/Fa_disulphide_b/1'>C-terminal half</scene> of the Noggin resembles the BMPs in that it have two pairs of <span style="color:red">'''antiparallel β-strands'''</span> extending out from a core containing <span style="color:yellow">'''disulphides bonds'''</span>. In contrast to BMP-7, binding of the monomer consists of <scene name='Sandbox_Reserved_429/Fa_helix_duo/2'>interaction</scene> between the <span style="color:blue">'''α4'''</span> of each monomer. When noggin binds to BMP-7, the tip of finger 1 and 2 in BMP-7 curls around the <span style="color:magenta">'''N-terminal'''</span> segment of the noggin.<ref>PMID: 12478285</ref>
| + | Overall Structure - name of team member |
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| - | BMP ligands have two prominent <scene name='Sandbox_Reserved_429/Hydropockects_fa/1'>hydrophobic patches</scene> 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 <scene name='Sandbox_Reserved_429/Pocket/2'>hydrophobic ring</scene> of <span style="color:black">'''Pro 35'''</span> of the noggin inserts into the hydrophobic pocket on BMP-7 formed by <span style="color:blue">'''Trp 52'''</span>, <span style="color:brown">'''Trp 55'''</span>, <span style="color:orange">'''Val 87'''</span>, <span style="color:green">'''Tyr 128'''</span>, and <span style="color:red">'''Met 131'''</span>.<ref>PMID: 12478285</ref> 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. 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.
| + | Drug Binding Site - name of team member |
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| - | 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.<ref>PMID: 11846481</ref>
| + | Additional Features - name of team member |
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| - | ===Additional Features===
| + | Quiz Question 1 - name of team member |
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| - | <Structure load='1m4u' size='500' frame='true' align='right' caption='Mutations of residues in BMP7 ' scene='Insert optional scene name here' />
| + | Quiz Question 2 - name of team member |
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| - | BMPs and their antagonists such as Noggin can affect developing chick limbs. Through experimentation, it was found that wild type – Noggin and
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| - | <span style="color:green">"Cys232 variant"</span> <scene name='Sandbox_Reserved_429/Chrondrogenesisinhibition/1'>inhibits chrondogenesis</scene> (formation of cartilage of developing limbs) but <span style="color:red">Pro35Arg</span> weakly inhibits chondrogenesis. <span style="color:tan">Glu48Lys</span>, <span style="color:red">Ile218Glu</span>, <span style="color:purple">Leu46Asp</span> Noggin <scene name='Sandbox_Reserved_429/3sitesnotinhibiting/1'>did not produce any changes</scene>. These variants also inhibits interdigital apoptosis in the same way. In this process, purified noggins was added to beads and exposed to developing chick limbs.
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| - | Mutations in human Noggin gene (NOG) cause changes in joint formation. If there are changes in positions of <span style="color:deepskyblue">Pro35Arg</span>, <span style="color:darkblue">Cys184Tyr</span>, <span style="color:brown">Gly189Cys</span>, <span style="color:green">Ile220Asn</span>, <span style="color:deepskyblue">Tyr222Cys</span>/Tyr222Asn, or <span style="color:red">Pro223Leu</span>, it is <scene name='Sandbox_Reserved_429/Mutations_sites2/3'>related to proximal symphalangism (SYM1)</scene>. Changes in positions of <span style="color:deepskyblue">Pro35Arg</span>, <span style="color:deepskyblue">Arg204Leu</span>, and <span style="color:deepskyblue">Tyr222Cys</span> is associated with tarsal/carpal coalition syndrome (TCC) and changes with <span style="color:orange">Trp217Gly</span> with multiple synostoses (SYNS1). Most of these changes can cause problem with joint formation and folding and stability. One particular mutation of interest is <scene name='Sandbox_Reserved_429/Pro35serp/1'>Pro35Ser mutation</scene> which is similar to Noggin Pro35Arg because it decreased binding affinities and lower inhibition of chrondogenesis. It is due to the structure of the polar hydroxyl group of <span style="color:purple">serine</span> that it is unable to bind to the hydrophobic pocket on the BMP. <ref>PMID: 12478285</ref>
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| - | ===Credits===
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| - | Introduction - Alec
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| - | Overall Structure - William
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| - | Drug Binding Site - Felix
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| - | Additional Features - Paula
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| | ===References=== | | ===References=== |
| | <references/> | | <references/> |
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| - | [i]http://www.pennmedicine.org/encyclopedia/em_DisplayAnimation.aspx?gcid=000112&ptid=17 | |
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| - | [iii]http://www.stryker.com/en-us/products/Orthobiologicals/Osteoinductive/OP-1/index.htm | |
