KinasePro

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

PDB Update

Posted by kinasepro on September 7, 2007

2E14 is ERK2 complexed to the macrocycle: FR-148083 via Astellas

BBRC: “Role of a cysteine residue in the active site of ERK and the MAPKK family”

O=C(C1=C(O[H])C=C(OC)C=C1/C=C/C[C@H](O)[C@@H]2O)O[C@@H](C)C\C=C/C2=O

related…

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16 Responses to “PDB Update”

  1. binding said

    The OH is binding to the hinge through O lone pair? or the OH? Is there a hinge residue flip here?

  2. This reminds me of some discussion at TotallyMedicinal which seems to have gone off the radar of late. One problem with adding a thiol to something like a nitrile or carbonyl is that you need to have polar functionality near the thiol to stabilise the polar adduct. Adding the thiol across the carbon-carbon double bond doesn’t create new polarity in the ligand and places few demands on the environment od the cysteine. These additions (I’m not sure if it can actually be called a Michael addition) are also reversible. The safety issue of cysteine adduct formation will remain but perhaps this can be managed.

  3. kinasepro said

    The phenol is the hinge hydrogen bond acceptor.

  4. JJ said

    Interesting! How can carbonyl oxyen of the compound be H-bounded to the amide oxyen of the hinge residue?

  5. kinasepro said

    I suspect the phenol and that carbonyl exist as a pseudo – 6 membered ring as the 2D representation suggests. That network might then be both hydrogen bond donor and acceptor. The dotted lines in the image were drawn somewhat arbitrarily…

  6. rosko said

    The distance between the ester carbonyl and the hinge carbonyl is 3.52 A, which is long for a hydrogen bond, even considering the somewhat low resolution of the structure (compare with 2.79 A for the phenol-hinge NH interaction). It seems that the ester may in fact be there for nothing other than as a spacer group.

  7. Very interesting structure. Thanks for posting.

  8. sks said

    I wonder if it could be the phenolate instead of the phenol?

  9. sks said

    another thing that i was hoping people would comment on is the oreintation of the enone? wouldn’t it be love to be more planar unless there is already a covalent bond with the cysteine? I haven’t gone over the paper with a toothcomb, but do they have direct proof or covalent linkage?

  10. TotallyMedicinal said

    Isn’t the ester stereocenter different in the two representations? [Looks to be R in the Xray and S in the chemical structure?]

  11. kinasepro said

    Heh, I think TM is right, I’ll check it out and modify as needed. Thats a bonus for open source science… On the enone – I think the PDB has some minor issues as the distance between the sulfur atom and the proximate carbon center suggest that there is indeed a bond there – though it isn’t drawn in the PDB.

  12. binding said

    It seems that the ester carbonyl should hurt the binding due to electrostatic repulsion with the hinge carbonyl. It might be interesting to remove the carbonyl and make the corresponding ether compound or cyclize the phenol and carbonyl to a pyridine ring.

  13. kinase novice said

    Seems like the covalent bond must be reversible, similar to wortmannin on pi3 kinase ( Chemistry & Biology Vol 14, Issue 3, p 321-328).

  14. kinasepro said

    Interestingly – the stereochemistry of the 2D image is accurate, while in the PDB appears to be assigned incorrectly.

  15. TotallyMedicinal said

    Well, it is at 3.0A resolution, so maybe just a refinement problem?

  16. kinasepro said

    Wull… trying to refine the wrong enantiomer might be a problem! But this is a good example of the limitation of crystallography, and the resolution certainly doesn’t help.

    To my eye there are a few minor issues with the PDB. a) the chiral center, b) the covalent bond, c) The former enone carbonyl carbon shouldn’t be SP2-planar, oh and of course d) the lactone ester should be ~2.9 A from the hinge ~~~

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