Create new version of Fig. 8 (or additional panel) for a third kinase

[jchodera]

We should add a new version of Fig. 8 showing the equivalent of Fig,. 8 for another kinase (maybe for DDR1?).

Reviewer comment:

• The example shown here is not very convincing, because the two conformations picked up by Ensembler are already crystallized. What would be more convincing is if Ensember can pick up dual conformations in other proteins whose structures are only found through template-based homologies, thus, providing a clear objective for using a multi-structure strategy over other current methods. Can Ensembler do this?

[danielparton]

Human DDR1 has 4 crystal structures. What about doing this analysis for a kinase with no crystal structures at all? This is the barchart showing the number of structures per TK target. And below is the list of TKs with no crystal structures. Any suggestions for an interesting kinase from this list, @sonyahanson ? Something with known disease importance?

BLK_HUMAN_D0
DDR2_HUMAN_D0
EPHA1_HUMAN_D0
EPHA4_HUMAN_D0
EPHA6_HUMAN_D0
EPHAA_HUMAN_D0
EPHB6_HUMAN_D0
FER_HUMAN_D0
FGR_HUMAN_D0
FLT3_HUMAN_D0
FRK_HUMAN_D0
INSRR_HUMAN_D0
JAK3_HUMAN_D0
LMTK1_HUMAN_D0
LMTK2_HUMAN_D0
LMTK3_HUMAN_D0
LTK_HUMAN_D0
MATK_HUMAN_D0
MUSK_HUMAN_D0
PGFRA_HUMAN_D0
PGFRB_HUMAN_D0
PTK6_HUMAN_D0
ROR1_HUMAN_D0
RYK_HUMAN_D0
SRMS_HUMAN_D0
STYK1_HUMAN_D0
TEC_HUMAN_D0
TIE1_HUMAN_D0
TNK1_HUMAN_D0
TXK_HUMAN_D0
TYRO3_HUMAN_D0
UFO_HUMAN_D0
VGFR3_HUMAN_D0
YES_HUMAN_D0

[sonyahanson]

Nothing jumps out at me.

DDR2 was suggested by @ritikakundra.

[jchodera]

Or maybe we want a TK without Xray structures? Or one of interest with only a single Xray structure?

[jchodera]

Have you checked your KinomeRank scores?

[danielparton]

Was just doing that :)

I think I will go with VGFR3_HUMAN, aka FLT4.

From UniProt:

[FLT4 plays an] important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases

UniProt also mentions involvement in a two other diseases.

39th in the KinomeRank table No structures of kinase domain 194 publications in PubMed 426 bioassays in BindingDB Fairly high mutation rate in cBioPortal data

I like the name KinomeRank btw :)

[jchodera]

I think I will go with VGFR3_HUMAN, aka FLT4.

Works for me!

I like the name KinomeRank btw :)

We should totally exploit that!

[danielparton]

Here's the new analysis for Flt4. Looks good to me. Note these figures will be the same scale in the manuscript. They are sized differently here due to the GitHub Markdown processor.

Src:

Abl:

Flt4: