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

PDB Update

Posted by kinasepro on October 16, 2007

2R9S is Jnk3 bound in an unusual fasion to a quinoline inhbitor:(Reminds me a little of Vertex’s 2ok1) (BMCL)

2NPQ is p38 bound to 2 molecules of octyl-glucoside:



6 Responses to “PDB Update”

  1. milkshake said

    This rather funny: I was typing an excited e-mail: “Hey bossman – just have a look at this beast!” but fortunately I clicked on the database link before sending the e-mail alert to everybody – and saw that this X ray is actually a structure from our group.

  2. Sulfonanamide conformation in 2r9s doesn’t look right. Normally CN is about 90 deg out of ring plane with Os on other side of plane. I wonder how well the electron density supports it.

  3. rosko said

    It was funny, I was just looking through the PDB and saw this structure. When I hovered my mouse over the molecule name to see the structure, I was only half-paying attention to the location of the quinoline nitrogen and thought mentally “Oh, another anilino quinazoline analog”. Then I took a look at the actual structure file and realized how unlike that it really was.

  4. TotallyMedicinal said

    I think the preference is for the S=O bond to be eclipsing the plane of the aromatic (maximising S-O sigma*-aromatic overlap?). This would normally put the CN bond approx. perpendicular to the plane of the aromatic.

    I think that introduction of an ortho subsituent (or two such substituents at the 2 and 6 positions) would favour the staggered conformer seen here – although obviously might have other effects on potency.

  5. Sulfonamide nitrogens are typically pyramidal with the ‘lone pair’ pointing towards the centroid of the oxygens. This means that whatever is on the nitrogen is pushed in the direction of the aromatic ring. I am a little sceptical of the crystallogapher’s model in this case and would certainly want to look at electron density is I were using this structure. All that said, a high energy bound conformation should always be seen as an opportunity.

  6. milkshake said

    I second the sulfonamide sp3 nitrogens – I have seen it pyramidal in all crystal structures.

    When it comes to detailed geometry (as opposed to large distance shape) one needs to be somewhat sceptic – if you get with scale down to the X-ray data resolution, things get blurry – so it is gonna be interpretation-dependent. I have seen even pyramidal amides in crystalography database – clearly an uncorrected artifact.

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