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Re: [ccp4bb] References for ligand flipping
 

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CCP4bb <-- 2008 <-- February 2008 <-- 19 February 2008
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Subject: Mosflm P21 integrating issues
From: Andrew Dore andrew {- dot -} dore {- at -} ICR {- dot -} AC {- dot -} UK
Date: 2008-02-19 		Next message:
Subject: Re: References for ligand flipping
From: David Komander dkomander {- at -} MAC {- dot -} COM
Date: 2008-02-19


Subject: Re: References for ligand flipping
From: "Ohren, Jeffrey" Jeffrey {- dot -} Ohren {- at -} PFIZER {- dot -} COM
Date: 2008-02-19
Kendall, All,



One classic example that comes to mind is the multiple binding modes
that have been structurally described for the drug Gleevec AKA Imatinib.
Gleevec or closely related analogs have been shown to bind to the
kinases Abl (1) and c-Kit (2) in a Phe-out conformation of the conserved
DFG-segment. However, Gleevec has also been shown to bind to the kinases
Syk (3) and c-Src (4) in a Phe-in binding mode that is significantly
different to the conformation observed in Abl and c-Kit kinase.



I'm sure there are many other examples out there...



Cheers,

Jeff



Jeffrey F. Ohren, Ph.D.

Principal Scientist

Pfizer Global Research and Development

Eastern Point Road

Groton, CT 06340



1) Schindler T, Bornmann W, Pellicena P, et al. Structural mechanism for
STI-571 inhibition of abelson tyrosine kinase. Science 2000; 289:
1938-42.

2) Mol CD, Dougan DR, Schneider TR, et al. Structural basis for the
autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. J Biol
Chem 2004; 279: 31655-63.



3) Atwell, S, Adams, JM, Badger, J, et al. A Novel Mode of Gleevec
Binding Is Revealed by the Structure of Spleen Tyrosine Kinase J. Biol.
Chem., Vol. 279, Issue 53, 55827-55832, December 31, 2004



4) Cowan-Jacob SW, Fendrich G, Manley PW, et al. The crystal structure
of a c-Src complex in an active conformation suggests possible steps in
c-Src activation. Structure 2005; 13: 861-71.

________________________________

From: CCP4 bulletin board [mailto:CCP4BB@JISCMAIL.AC.UK] On Behalf Of
Kendall Nettles
Sent: Monday, February 18, 2008 9:10 PM
To: CCP4BB@JISCMAIL.AC.UK
Subject: Re: [ccp4bb] References for ligand flipping



Jon, I have not had any replies. I did hear a talk at an American
Chemical Society meeting on a ligand flipping between the two estrogen
receptor subtypes, but it hasn't been published from what I can tell.
Here's a link to the abstract.

membership.acs.org/C/COMP/pastprograms/Fall06abstracts.pdf

Kendall


On 2/18/08 8:38 PM, "Read, Jon" wrote:

Hi Kendall,
did you get any replies about this as I would be interested in hearing
about these. I have seen some talks of kinases which mention this but
can't recall the targets.


-----Original Message-----
From: CCP4 bulletin board [mailto:CCP4BB@JISCMAIL.AC.UK]
On Behalf Of Kendall Nettles
Sent: Saturday, February 09, 2008 11:04 AM
To: CCP4BB@JISCMAIL.AC.UK
Subject: [ccp4bb] References for ligand flipping



Hi,
Thanks to everyone for suggestions on making disulfides. I do have
another
question.

Can anyone suggest some references for structures showing that a small
molecule ligand binds differently in closely related proteins?


Thanks,
Kendall
--
Kendall W. Nettles, PhD
Assistant Professor
Department of Cancer Biology
The Scripps Research Institute
5353 Parkside Dr.
Jupiter Fl 33458
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