New B12-Insulin-TCII-Insulin Receptor Cover Image For This Month's ChemMedChem (March 2009)

As was the case for the first ChemMedChem December, 2007 cover issue (posted previously), the cover story in this month's issue is a communication by myself and members and collaborators of the Robert Doyle Group here at Syracuse University.  In this case, the work for the cover image actually went into computational research published in the associated article (instead of just a pretty cover image to complement the associated article, which was the intent of the previous cover).

The image below shows the Transcobalamin II (TCII) protein (in teal ribbons, with a bound cyanocobalamin (B12) shown in red.  The PDB code for this complex is 2BB5) sitting within the surface-accessible fragment of the gigantic insulin receptor (PDB code 2DTG.  The cell membrane would be at the bottom of this image, with the remainder of the complete protein sitting both within the cell membrane and then into the cytoplasm).  Saving the lead-up to this structure generation for the associated published article, this image was created to show one of the most important steps in the Oral Insulin project being worked on in the Doyle Group, with the fact that we know it works making the validity of the image content all the more relevant.  In brief, this figure shows that the TCII/B12-Insulin complex can fit within the insulin receptor such that the insulin molecule can bind to its receptor position on the appropriately described insulin receptor (IR), thereby instigating the cascade of events that leads to cellular glucose uptake.

For a larger view, click on the image.

Like many of the protein structures I render, this image would not have been possible without VMD and MegaPOV, my favorite OSX POV-Ray variant (there's quite a bit of Photoshop layering as well).  The final layout for the cover is below, which I think would have benefited from the aerial view on the upper left side being shifted slightly to the left to fill out the black square.

According to the ChemMedChem website:

The cover picture shows three views of a vitamin B12-insulin conjugate bound to transcobalamin II, docked in the insulin receptor (IR). This study reveals how the structure of an orally deliverable insulin changes in solution after vitamin B12 conjugation and its effect on IR binding capacity. The results demonstrate that chemical modification of insulin by linking relatively large pendant groups does not interfere with IR recognition. For more details, see the Full Paper by T. J. Fairchild, R. P. Doyle, et al. on p. 421 ff.

To date, the associated work has received some additional linkage, both in the form of inclusion in the Spotlight list in Angew. Chem. Int. Ed. 2009, 48, 2072 – 2073 and, for those looking for a more pop-sci discussion of the applications of the research, New Scientist (Insulin Chewing Gum, 14 January 2009).  PDFs of the associated content are provided here for Angewandte Chemie and New Scientist.

There is a considerable amount of additional computational work being done on this system and the complete B12 pathway for potential use in various other applications.  Stay tuned for next year's cover.

www3.interscience.wiley.com/journal/110485305/home
www3.interscience.wiley.com/journal/117354609/issue
www.somewhereville.com/?p=103
chemistry.syr.edu/faculty/doyle.html
www.syr.edu
en.wikipedia.org/wiki/Transcobalamin
en.wikipedia.org/wiki/Cyanocobalamin
www.rcsb.org/pdb/home/home.do
www.rcsb.org/pdb/explore/explore.do?structureId=2BB5
en.wikipedia.org/wiki/Insulin_receptor
www.rcsb.org/pdb/explore/explore.do?structureId=2DTG
en.wikipedia.org/wiki/Cytoplasm
en.wikipedia.org/wiki/Insulin
www.ks.uiuc.edu/Research/vmd
megapov.inetart.net
www.apple.com/macosx
www.povray.org
en.wikipedia.org/wiki/Adobe_Photoshop
www3.interscience.wiley.com/journal/122232189/issue
www.newscientist.com/article/dn16413-invention-insulin-chewing-gum.html

Oral Insulin Delivery Cover Image (And Associated Syracuse Research Article) in ChemMedChem

You've heard about it, you've read about it, you've seen it on color TV, you've even seen it streamed. The cover story in this month's issue of ChemMedChem is a communication by members and collaborators of the Robert Doyle Group here at Syracuse University. The report describes the B12/TCII-based uptake of insulin, a process that occurs via the ingestion of a B12-insulin conjugate. In case you missed that, the delivery is oral, not by needle. For those of us that pass out at anything needle-related at about the time that the alcohol wipe is opened, that's a positive step forward for getting rid of any syringe-related medicine altogether.

full image

With the cover story comes the cover image shown above, a structure calculation on the insulin-B12/TCII complex. The bases for this structure can be found in the Protein Data Bank, including the TCII-B12 complex reported in PDB entry 2BB5 (the only hack in the structure calculation involved the replacement of the cobalt for iron to use already available bond parameters) and the insulin structure reported in PDB entry 1ZNI. The covalent attachment of the insulin to B12 can be found in the article. Structure manipulation was performed with a combination of NanoEngineer-1 and VMD, VMD being included in the mix in order to generate the ribbon renderings of the insulin and TCII protein backbones. As for the accuracy of the calculation, time and a synchrotron X-ray source will tell.

For much more information and numerous links to new stories related to the research in the article, I direct you to the group website of Robert Doyle and the various links to news stories available in his departmental publication list.

chemmedchem cover
From ChemMedChem. Click HERE to go to the article.

From the website:

Cover Picture: Vitamin B12 as a Carrier for the Oral Delivery of Insulin (ChemMedChem 12/2007). The cover picture shows an orally active, glucose-lowering vitamin B12-insulin conjugate bound to the B12 uptake protein transcobalamin II (TCII). The inset shows a close-up view of the TCII binding pocket. (Insulin is in red; vitamin B12 is in bright yellow.) For details, see the Communication by T. J. Fairchild, R. P. Doyle, et al. on p. 1717 ff.

www3.interscience.wiley.com/journal/110485305/home
chemistry.syr.edu/faculty/doyle.html
www.syr.edu
www3.interscience.wiley.com/cgi-bin/abstract/117354616/ABSTRACT?CRETRY=1&SRETRY=0
en.wikipedia.org/wiki/B12
en.wikipedia.org/wiki/Insulin
en.wikipedia.org/wiki/Transcobalamin
www3.interscience.wiley.com/journal/117354609/graphissue
www.rcsb.org/pdb
www.rcsb.org/pdb/explore.do?structureId=2BB5
www.rcsb.org/pdb/explore.do?structureId=1ZNI
www.nanorex.com
www.ks.uiuc.edu/Research/vmd
en.wikipedia.org/wiki/Synchrotron
chemistry.syr.edu/faculty/doyle_group/index.html
chemistry.syr.edu/faculty/doyle.html#pubs