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	Overall Structure - Katie Kwan		Overall Structure - Katie Kwan
-	Drug Binding Site - name of team member	+	Drug Binding Site - Ishtiaq Rafi
	Additional Features - name of team member		Additional Features - name of team member

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Revision as of 18:14, 29 February 2016

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 1 Protein complex with cancer drug Alecensa-Alectinib (4uxl)[1] 2 Introduction 3 Overall Structure 4 Binding Interactions 5 Additional Features 6 Quiz Question 1 7 See Also 8 Credits 9 References

Protein complex with cancer drug Alecensa-Alectinib (4uxl)^[1]

by Laura Feeley, Katie Kwan, Daniel Peters, Ishtiaq Rafiyu, Luke Ruksnaitis

Student Projects for UMass Chemistry 423 Spring 2016

Introduction

(Laura)

-Alectinib is an inhibitor of oncogenic c-ros oncogene1 (ROS1) fusion kinases as well as anaplastic lymphoma kinase (ALK). (insert green scene of protein bound to ligand, linking on the word Inhibitor)

-It is a second generation drug that differs from the kinase inhibitor drugs preceding it, in that it's aim is to fight resistance to the inhibitor drugs that occur through mutations (key features/what makes it different)

-This inhibiting complex is likely to be effective in non-small cell lung cancer and other ROS1 fusion-positive cancers

- It is an ATP-competitve inhibitor

-Having difficulties inserting new scene

spinqualitylabelsall models 4uxl, Insert caption here Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

spinqualitylabelsall models 4uxl, Ligand (Green) Bound to Complex Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Overall Structure

b. Overall structure (Katie) Describe the overall structure of your protein in words and make "green scenes" to illustrate your points.

What elements of secondary structure are present (ie 5 alpha helices and 2 beta strands) and how are they organized?

-The Human ROS1 Kinase Domain in Complex consists of a small N-terminus lob and a large C-terminus lobe. The N-terminus lobe contains a 5 stranded antiparallel bets sheet and an alpha helix.

-The C-terminus lobe consists mainly of an alpha helix which contains 6 segments, as well as 2 conserved beta strands. This lobe has helical structure and is there the regulatory activation loop is located.

Additional description and green scenes could illustrate the polar/nonpolar distrubution of amino acids (is the inside of the barrel polar or nonpolar?), packing of amphipathic elements, etc.

Ligand 5p8: (10r)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2h-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile 289 amino acids

spinqualitylabelsall models 4uxl, Overall Structure Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Binding Interactions

c. Binding interactions Describe features of the drug or ligand or protein-protein binding site in words and make "green scenes" to illustrate your points. Show the interactions that stabilize binding of this molecule to the protein (ie H bonds).

spinqualitylabelsall models pdbcode, Insert caption here Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Additional Features

d. Additional features Describe and use green scenes to illustrate additional features of the macromolecule. What you do here depends on what information is available. If a structure of the protein-substrate complex is available, you could compare protein interactions with the substrate vs. with the drug. If the drug is a transition state inhibitor, explain and illustrate that (eg include a reaction scheme with structures of the substrate, transition state and product -- but don't borrow a published scheme).

spinqualitylabelsall models pdbcode, Insert caption here Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Quiz Question 1

e. Quiz question Pose an interesting, quiz-worthy question that involves thinking and investigating the molecule with the green scenes that you provide here. Submit the answer to your question in Moodle and do not share it with other students. Best questions will be chosen for a Moodle quiz, so that students can explore your structure and green scenes to figure out the answer to your quiz question.

spinqualitylabelsall models pdbcode, Insert caption here Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

See Also

[Structure of Human ROS1 Kinase Domain in Complex]

[Tyrosine kinase]

Credits

Introduction - Laura Feeley

Overall Structure - Katie Kwan

Drug Binding Site - Ishtiaq Rafi

Additional Features - name of team member

Quiz Question 1 - name of team member

References

1. ↑ Zou HY, Li Q, Engstrom LD, West M, Appleman V, Wong KA, McTigue M, Deng YL, Liu W, Brooun A, Timofeevski S, McDonnell SR, Jiang P, Falk MD, Lappin PB, Affolter T, Nichols T, Hu W, Lam J, Johnson TW, Smeal T, Charest A, Fantin VR. PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations. Proc Natl Acad Sci U S A. 2015 Mar 2. pii: 201420785. PMID:25733882 doi:http://dx.doi.org/10.1073/pnas.1420785112