Fwd: Knocking off HSPs. How?

Nora Plesofsky nora at biosci.cbs.umn.edu
Thu May 9 15:20:14 EST 2002

A specific inhibitor of Hsp90 and its binding (along with other Hsps) to 
steroid receptors is geldanamycin.

Nora Plesofsky

> From: alansmith at students.wisc.edu
> Date: Thu May 09, 2002  02:05:49 PM US/Central
> To: proteins at hgmp.mrc.ac.uk
> Subject: RE: Knocking off HSPs. How?
> Hi,
> There was a paper published in a 1998 Nature entitled: HSP90 as a 
> capacitor
> for morphological evolution. They used a specific inhibitor of HSP90
> developed as a cancer medication.  Its a great article too.
> Alan Smith
> -----Original Message-----
> From: owner-proteins at hgmp.mrc.ac.uk
> [mailto:owner-proteins at hgmp.mrc.ac.uk]On Behalf Of Emir Khatipov
> Sent: Thursday, May 09, 2002 11:01 AM
> To: proteins at hgmp.mrc.ac.uk
> Subject: Re: Knocking off HSPs. How?
> "D.K." <dk at no.email.thankstospam.net> wrote in message
> news:abcv6s$q9u$1 at news.doit.wisc.edu...
>> "Emir Khatipov" <khatipovNO at NOuchicago.edu> wrote:
>>> I would appreciate if someone could help me to solve a rather tricky
> riddle.
>>> When not bound to steroids, steroid receptors (SRs) form complexes with
> heat
>>> shock proteins (HSPs) in the cytoplasm. Upon activation with steroids,
> the
>>> receptors change conformation, lose the coat of HSPs and penetrate the
>>> nucleus to activate transcription of target genes.
>>> Does anybody know or could come up with an idea how to dissociate SRs
> from
>>> HSPs by some physical or chemical stimulation?
>>> The reason I am asking is the following. I am trying to develop 
>>> compounds
>>> (small molecules, including peptides) that would bind SRs in inactive
> form.
>>> I am a priori concerned that due to sterical hindrances those compounds
> will
>>> not be able to bind inactive SRs associated with HSPs, so I am trying to
>>> examine if there is anything known about the ways to dissociation these
>>> complexes in vivo. I tried to search literature on the subject, but did
> not
>>> dig out anything useful so far.
>> Emir,
>> The easiest way to dissociate these complexes is to add steroids :-)
>> No, seriously: add your compound X with a not so potent steroid
>> (one that has lower affinity for SR). Whether or not your concerns
>> are justified, doing this should allow you to screen for a potent
>> inhibitor of steroid translocation into nucleus.
> It's not an inhibitor of translocation I am looking for, but a specific SR
> binder that can be used for tissue-specific targeting of (e.g.) drugs (not
> necessarily SR-related ones). Some SRs are good tissue-specific markers. 
> If
> I am not lucky enough, the first compounds I screen will have weaker
> affinity to SRs than the weakest steroids, and I will have to apply
> factorial structure-function analysis to design stronger binders. Another
> problem is that the weaker binding steroids, as well as many other 
> steroids,
> are controlled substances and are not available on the market (at least as
> far as I know).
> Is there anything known about how HSP's binding to proteins is affected by
> redox potential, drugs, interactions with other proteins, temperature, 
> etc.?
> Chemicals ot physical factors might be easier to explore. However,
> biological approach might work as well. For example, there could be a
> protein P that can interact with HSP and cause dissociaton of the latter
> from the SR. By controlling levels of P it would be possible to affect
> binding of SR to HSP and thus allow compound X to bind SR. I have quite a
> limited knowledge on HSPs, and assume that the reason I did not find any
> relevant information so far in a vast amount of literature on HSP is 
> because
> the papers I am looking for are among those "shy" ones that never get
> referenced in databases....
> Any more ideas?
> Emir
>> Anything wrong with such approach? Of course you'll get lots
>> of inhibitor that block other steps, but this _always_ happen
>> whenever you attempt to do anything in vivo.
>> DK
> ---


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