Thank you, oh collective memory that is CCP4BB!
Last week I posted the following question:
On Mon, 11 Apr 2016, Gerard DVD Kleywegt wrote:
> Hi all,
>
> In 2002 I asked the BB a question to which I received many useful responses,
> showing the power of crowd-sourcing (although that term didn't exist yet at
> the time I think) - http://www.ysbl.york.ac.uk/ccp4bb/2002/msg00887.html
>
> Now I would like to pick the collective CCP4 Bulletin Brain again:
>
> Does any of you know of any examples (available in the PDB) where the same
> ligand is observed in two distinctly different conformations (with convincing
> support in the density) in one and the same structure (i.e., same PDB entry)?
> This could for example be two copies of a ligand bound to a dimer in
> different poses. I'm interested only in distinct sites, not multiple
> conformations in one site.
>
> I will happily summarise the replies.
>
> Best wishes,
>
> --Gerard
The replies I have received are listed below. Thanks to everybody who took the
time to reply. You have provided ample pabulum (meaning 2, not 3!, in
Merriam-Webster).
Best wishes & toodle pip!
--Gerard
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From: Hanno Sjuts <[log in to unmask]>
doxorubicin binding to AcrB might be such an example, pdb id 4DX7.
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From: James Hall <[log in to unmask]>
This may not be looking for but I have a DNA structure containing the two
enantiomers of the same Ru-polypyridyl complex bound to a single DNA sequence.
The PDB ID is 4JD8.
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From: Francis Reyes <[log in to unmask]>
Two molecules of THF in the THF riboswitch, Maybe not too different of a
conformation, however.
Follow-up email:
D'oh, a PDB link might be useful.
http://www.rcsb.org/pdb/explore/explore.do?structureId=4LVV
Reply:
I prefer pdbe.org/4lvv :-)
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From: Jeffrey B Bonanno <[log in to unmask]>
PDB entry 1PTY, CRYSTAL STRUCTURE OF PROTEIN TYROSINE PHOSPHATASE 1B COMPLEXED
WITH TWO PHOSPHOTYROSINE MOLECULES
Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13420-5. Identification of a
second aryl phosphate-binding site in protein-tyrosine phosphatase 1B: a
paradigm for inhibitor design. Puius YA1, Zhao Y, Sullivan M, Lawrence DS,
Almo SC, Zhang ZY.
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From: "Carter, Charlie" <[log in to unmask]>
You raise a challenging question that I?ve thought some about because of
evidence that the two binding sites of the two TrpRS monomers in tetragonal
crystals grown with tryptophan and ATP are not occupied in the same way,
despite the fact that the asymmetric unit is a monomer.
We?ve never really worked out what happens beyond this: The crystals diffract
only to ~3.0 ?, and radio labeling with 13C Trp and 32Pgamma ATP shows that
there is one molecule of ATP, two molecules of Tryptophan per dimer. We
previously argued that the crystals are disordered because the active sites
have disproportionate to give one with Trp-5?AMP and one with Trp-2?-3?ATP.
If we incubate the crystals (grown in Phosphate) in ammonium sulfate, we get a
phase transition to give ultra fractured crystals with new unit cell
dimensions, that diffract to at least 1.6 ? and have one molecule of Trp-5?AMP
in both active sites at full occupancy.
This isn?t what you asked, exactly, but it does illustrate that something of
the sort you imagine might happen. Sorry I cannot provide details or give
evidence of a better example.
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From: Patricia Legler <[log in to unmask]>
We recently published a bis-oxime bound to acetylcholinesterase (two 2-PAM
molecules linked together with a carbon linker). This trick effectively traps
the molecule bound to 2 different sites (this is also an example of
allosterism, binding of 2PAM at the top of the gorge affects the conformation
of 2PAM at the bottom of the gorge). Ortho-7 was intended to be a drug, it
binds AChE tightly by binding the enzyme at both sites (Ki is I the mid-nM
range). 2-PAM on its own binds much weaker (high uM). Ortho-7 is really
toxic. Other linker lengths were tested prior to selecting Ortho-7 (7-carbon
linker).
There are 2 distinct sites for the same molecule (2-PAM): One binding site is
at the top of the gorge, the 2nd at the bottom of the gorge (see Fig. 4).
The same molecule also bound in one conformation in acetylcholinesterase from
T. californica (the oxime is aligned for attack in this conformer), and in a
2nd conformation in mouse AChE (the oxime is rotated away from the active site
and is unable to attack, this is an inhibitory conformer). These two enzymes
only have one difference (Phe/Tyr in the gorge).
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From: Gloria Borgstahl <[log in to unmask]>
Gerard, the E. coli MnSOD crystals present 4 unique active sites with
different peroxide orientations
Structural analysis of peroxide-soaked MnSOD crystals reveals side-on binding
of peroxide to active-site manganese.
<http://www.ncbi.nlm.nih.gov/pubmed/20417642>
Porta J, Vahedi-Faridi A, Borgstahl GE.
J Mol Biol. 2010 Jun 11;399(3):377-84. doi: 10.1016/j.jmb.2010.04.031. Epub
2010 Apr 24.
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From: Mark A Saper <[log in to unmask]>
1ABE - L-arabinose binding protein with both alpha and beta anomie?s of
arabinose in the binding site. I don?t think the data is available for this,
but I have a high-resolution figure (from the paper) showing the electron
density. Contact me off-list.
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From: H. Raaijmakers <[log in to unmask]>
Maybe so, with indirect evidence that it once did: In the 2w8y progesterone
receptor dimer, the conformations/affinity were different enough that one was
selectively replaced by soaking. In one of the (unpublished) soaks with a
rather small ligand, only the compound in the other chain was replaced, so,
access to solvent channels can't explain all of it.
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From: Joel Tyndall <[log in to unmask]>
Indeed I have published one.... 3WNR. A separate structure 3WNT showing three
similar conformations.
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From: Tom Huxford <[log in to unmask]>
We saw the curare drug metocurine bound in completely different orientations
to neighboring binding sites in the crystal of a pentameric acetycholine
binding protein from saltwater snail. I never did publish on this but I
submitted the coords to the PDB (3PEO). It's been a long time since I've
thought about this and I'd be interested to hear your opinion if you have the
time to give it a look.
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From: Kendall Nettles <[log in to unmask]>
Look at my last two Nature Chemical Biology papers and eLife paper. We have a
few more coming out soon.
Follow-up email:
From: Jerome Nwachukwu <[log in to unmask]>
Here are the PDB codes:
4PP6 (eLife 2014)
4IW8 (Nat Chem Biol 2013)
4IWF (Nat Chem Biol 2013)
3OSA (Nat Chem Biol 2010)
3OS8 (Nat Chem Biol 2010)
3OS9 (Nat Chem Biol 2010)
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From: Demetres D. Leonidas <[log in to unmask]>
3MTD
Follow-up email:
The pdb is from a series of thiosemicarbazone derivatives in complex with
glycogen phosphorylase. In the pdb entry 3MTD there are two thiosemicarbazone
derivatives bound (ID 25E) one with E and one with Z configuration in two
different binding sites (catalytic and new allosteric).
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From: GIGANT Benoit <[log in to unmask]>
3HQE: one covalent binding, one non-covalent. 3.6 Ang resolution only, but
there was prior biochemical evidence for the two binding modes.
2XI3
1Q90
I hope these are relevant examples.
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From: Kittikhun Wangkanont <[log in to unmask]>
Please check out 4WMY. I'm rather convinced that in this case the different
poses have to do with crystal contact. We may have discussed about this
somewhere in the paper:
http://www.nature.com/nsmb/journal/v22/n8/full/nsmb.3053.html
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From: Vanessa Delfosse <[log in to unmask]>
3UUA, Crystal structure of hERa-LBD (Y537S) in complex with bisphenol-AF
<http://www.rcsb.org/pdb/explore/explore.do?structureId=3UUA>
Structural and mechanistic insights into bisphenols action provide guidelines
for risk assessment and discovery of bisphenol A substitutes. (2012)
Proc.Natl.Acad.Sci.USA *109*: 14930-14935
Reply:
Although I prefer to look at http://pdbe.org/3uua :-)
Follow-up email:
Thanks for the link, I was not used to look at PDBe but I think I will change!
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From: "Yelland, Tamas" <[log in to unmask]>
I believe the structure PDB: 3I97 fulfils the criteria
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From: "Agnew, Christopher" <[log in to unmask]>
PDB: 3R9C
Two Econazoles bound in the active site of CYP164A2. One econazole is bound
classically to the heme, a second econazole is bound to an adjacent metal ion
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From: Clemens Steegborn <[log in to unmask]>
We had that once, three molecules 4,4'-Diisothiocyano-2,2'-stilbenedisulfonic
acid bound to our target: PDB ID 4CLZ
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From: Marco Mazzorana <[log in to unmask]>
not sure 1ZOG is one such structure: inhibitor bound to the active site in 2
poses (40%:60% occupancy) rotated by 60 degrees but on the same plane.
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