KinasePro

Kinase Chemistry – Just a year and a half behind the times.

PDB Update

Posted by kinasepro on April 3, 2007

2OZA P38a – MK2 co-crystal

Harvard’s got a series of ligated EGFR mutants:
Cancer Cell ’07, 11 (3) 217 (doi busted?)

2ITN – G719S – AMP-PNP
2ITO – G719S – Iressa (quinazoline)
2ITP – G719S – AEE788 (pyrrolopyrimidine)
2ITQ – G719S – Staurosporine
2ITT – L858R – AEE788 (pyrrolopyrimidine)
2ITU – L858R – Staurosporine
2ITV – L858R – AMP-PNP
2ITW – L858R – Staurosporine
2ITX – WT – AMP-PNP
2ITY – WT – Iressa (quinazoline)
2ITZ – L858R – Iressa (quinazoline)
2J6M – WT – AEE788 (pyrrolopyrimidine)

The wild types are Glycine and Leucine 719 and 858, the mutants are Serine (orange) and Arginine (pink) respectively.

COC1=CC(NC=N\2)=C(C=C1OCCCN3CCOCC3)C2=N/C4=CC=C(F)C(Cl)=C4

“Strikingly, direct binding measurements show that gefitinib binds 20-fold more tightly to the L858R mutant than to the wild-type enzyme.”

Interesting… ‘nother ‘haven’t read the article yet’ observation, but from the PDB I’m guessing the arginine locks down the a-loop with two new hydrogen bonds. For some reason this is conformation is both more catalytically active and the quinazoline prefers it. I’ll be interested to see the activity of AEE788 against the same mutant.

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