From Proteopedia

Revision as of 20:31, 12 March 2015

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***We may want to consider changing our pdb code to 4c9x rather than 4c9w. The only difference between them is which enantiomer of crizotinib MTH1 is binding to. 4c9w = R and 4c9x = S. The S enantiomer is the one that causes inhibition. --Matt

OurMolecule

Introduction

This is a sample scene created with SAT to by Group, and another to make of the protein.

MTH1, also known as 7,8-dihydro-8-oxoguanine triphosphatase is an enzyme in the human body encodet by the NUDT1 gene.

MTH1 is an enzyme also know as 7,8-dihydro-8-oxoguanine triphosphatase that in the human organism is encoded by the NUDT1 gene. It is inhibited by (S)-Crizotinib which induced an increase in DNA single-strand breaks, activated DNA repair in human colon carcinoma cells, and effectively suppressed tumor growth in animal models.

Binding Interactions

- Crizotinib inhibits kinases, which phosphorylate proteins

- (S)-crizotinib is a nanomolar MTH1 inhibitor, which indicates that (S)-crizotinib specifically inhibits MTH1

- The (S)-enantiomer of crizotinib is at least one order of magnitude more effective at inhibiting MTH1 (a kinase) than the (R) enantiomer

- An eclipsed conformation of a methyl group at the chiral center and a chlorine attached to the benzyl ring reduces the energetic favorability of (R)-crizotinib

- The specificity of (S)-crizotinib over (R)-crizotinib to inhibit MTH1 is NOT due to differences in binding interactions with the protein

- Crizotinib is acts on MTH1 through COMPETATIVE inhibition within the ATP binding pockets of targeted kinases

Additional Features

Quiz Question 1

- This scene colors the protein from the N-terminus to the C terminus.

- This scene colors nonpolar residues grey, polar residues red, and ligands bound to the protein green.

Close up of binding interaction - To be made.

Potential Questions:
-Would this protein be expected to embed itself in the cell membrane? Why?
-TBD
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-The questions are expected to have multiple parts, yes?

Quiz Question 2

-If this protein binds to the active site of MTH1 is it competive or non competitive?




- What effect on the functionality of MTH1 would this have?




-Judging by the active site of the complex, why does the (S) enantiomer exhibit more affinity for MTH1 then the (R) enantiomer?




- If this question is too difficult, could ask something else like what features of the active site attract the crizotinib inhibitor.




-I think here it would be best to show a close up ball and stick of the active site, one with hydrophobic representation, another with charges and one just showing the molecules.

See Also

• MTH1 (7,8-dihydro-8-oxoguanine triphosphatase)

Credits

Introduction - Megi Marina

Overall Structure - Cassandra Martin

Drug Binding Site - Ben Ryter

Additional Features - Colin Hannahan

Quiz Question 1 - Matt Tuttle

Quiz Question 2 - Eric Rice

References

[http://www.nature.com/nature/journal/v508/n7495/pdf/nature13194.pdf Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy - Huber] http://en.wikipedia.org/wiki/NUDT1 https://us.axonmedchem.com/product/2296/?SID=5c93d8ee559b459b8b412a1c15d92d8c&country_id=US http://news.medlive.cn/uploadfile/20140403/13965160178017.pdf