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From Proteopedia

Revision as of 20:55, 15 April 2012

YourMacromolecule

Introduction

1. Basic info (size, ligand name)

2. Origin (Zebrafish?)

3. Relation to disease (Metastatic Prostate cancer, kidney disease)

4. Pharmaceutical Applications

Overall Structure

1. Size of Protein

2. AA distribution

3. How many Domains

4. Number and locations of Alpha Helices, Beta Strands

5. Other pieces (non AA)

6. Primary Structure? Secondary? Tertiary?

Binding Interactions

Draft

BMP-7 uses two pairs of antiparallel β-strands 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 dimer. Free BMP-7 shows conformational changes in the "wrist" and "knuckles" areas upon complexing with receptors. [A]

Signaling by BMP-7 occurs by the binding of the protein to high affinity type II receptor (at the knuckle 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.

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.

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.

Outline

1. BMP7-Noggin Complex

2.Conformational changes due to binding

3. Hydrophilic and hydrophobic pockets

4. Receptor 1 & 2 and Finger 1 & 2

5. Others Antagonist of BMP 7

6. Binding affinity in comparison to others BMP families

7. Overall Summary of how binding affects overall pathways for bone formation

Additional Features

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