1 / 7

vFLIP-IKK g Blocker

vFLIP-IKK g Blocker . Edith Chan WIBR. IKK g. NF- k B Pathway. The Nf- k B pathway is related to inflammatory responses, cell death, and oncogenesis. Kaposi’s sarcoma herpesvirus (KSHV) encoded FLIP (vFLIP) binds to IKK g to activate NF k B.

sonora
Download Presentation

vFLIP-IKK g Blocker

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. vFLIP-IKKg Blocker Edith Chan WIBR

  2. IKKg NF-kB Pathway • The Nf-kB pathway is related to inflammatory responses, cell death, and oncogenesis. • Kaposi’s sarcoma herpesvirus (KSHV) encoded FLIP (vFLIP) binds to IKKg to activate NFkB. • Similarly, in human, cFLIP can associated with IKKg and thus has a wider application in cancer therapies.

  3. Work Study • The study focuses on using X-ray crystal structures, biophysical screening and structure based design to identify blockers of the vFLIP-IKKg and p22-cFLIP-IKKg interaction, conducting lead optimisation and identifying a development candidate. • My immediate actions are • Understanding of the interaction of the vFLIP-IKKg complex using X-ray crystal structure • Selection of compounds mimicking the IKKg interaction of the complex

  4. vFLIP C-terminus IKKg N-terminus E B A D X-ray crystal structure • Our collaborators at BBK have solved the structure between vFLIP-IKKg (3cl3). • Full length IKKg is 419aa long mulitdomain protein • Both proteins are truncated • ks-vFLIP (aa1-178) [188aa] • IKKg (aa150-272) [419aa] • The X-ray structure comprised of a dimer of two ks-vFLIP-IKKg complex. • The two vFLIP molecules come together solely through interactions between the two IKKg chains.

  5. Protein-Protein Interactions • Each of the IKKg helix is interacting with a copy of the vFLIP via two adjacent vertical clefts (cleft 1 and 2) • Cleft 1 involved more interactions between the complex, the hottest spot seems to be around Phe238 (of IKKg)

  6. 226 246 193QQHSVQVDQLRMQGQSVEAALRMERQAASEEKRKLAQLQVAYHQLFQEYDNHIKSSVVGSE253 Peptide tool compound vFLIP • Full length IKKg is 419aa long mulitdomain protein. In the X-ray structure, only the HLX2 (helix) domains (aa193-253) are co-crystallized with ks-vFLIP. • As seen from the picture, only a portion of the IKKg is interacting with vFLIP. They are about 20aa long as highlighted in a pink box. • Our first step is to use of peptide as proof of concept tool in further experiments • Can a shorter peptide of IKKg be sufficient to bind with vFLIP? • Can a shorter peptide adopt helical conformation on its own or by recognition to vFLIP? C-terminus N-terminus IKKg

  7. 226 238 246 193QQHSVQVDQLRMQGQSVEAALRMERQAASEEKRKLAQLQVAYHQLFQEYDNHIKSSVVGSE253 1 QQHSVQVDQLRMQGQSVEAALRMERQAASEEKRKLAQLQVAYHQLFQEYDNHIKSSVVGSE 2 QQHSVQVDQLRMQGQSVEAALRMERQAASEEKRKLAQLQVAYHQLFQEYDNHIKSSVVGSE 3 QQHSVQVDQLRMQGQSVEAALRMERQAASEEKRKLAQLQVAYHQLFQEYDNHIKSSVVGSE 4 QQHSVQVDQLRMQGQSVEAALRMERQAASEEKRKLAQLQVAYHQLFQEYDNHIKSSVVGSE 5 QQHSVQVDQLRMQGQSVEAALRMERQAASEEKRKLAQLQVAYHQLFQEYDNHIKSSVVGSE Proposed tool Peptides LengthAA spin • Longer peptide include C-terminus 30aa aa224-253 • Spin the entire interaction with vFLIP 21aa aa226-246 • Peptide that covers cleft1 interaction 16aa aa231-246 • Peptide that covers cleft2 interaction 15aa aa226-240 • Peptide that covers all essential interaction 12aa aa231-242

More Related