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:[EMAIL PROTECTED] 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" <[EMAIL PROTECTED]> 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:[EMAIL PROTECTED] <mailto:[EMAIL PROTECTED]> 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
