I am trying to understand why some drugs bind only to the minor groove and not to the major groove. More specifically, I am interested in calicheamicins.

They target DNA and cause strand scission. Calicheamicins bind with DNA in the minor groove, wherein they then undergo a reaction analogous to the Bergman cyclization to generate a diradical species. This diradical, 1,4-didehydrobenzene, then abstracts hydrogen atoms from the deoxyribose (sugar) backbone of DNA, which ultimately leads to strand scission.[7] The specificity of binding of calicheamicin to the minor groove of DNA has been demonstrated.

  • $\begingroup$ It would be helpful if you could provide a source for the extract you quote, preferably with a link. $\endgroup$ – David May 13 at 12:13
  • $\begingroup$ this particular quote is from wikipedia, en.wikipedia.org/wiki/Calicheamicin $\endgroup$ – marilu May 13 at 15:23

Accommodation in the major or minor groove

I am not in a position to generalize about all drugs that bind to the major groove of DNA, but at least one well-known example, actinomycin D, does so because it intercalates between the base-pairs in the double helix. Although other weak chemical interactions stabilize this binding, much of it is through base stacking with base-pairs. Hence binding requires it be inserted into the major groove in which the base pairs lie (see e.g. PDB 101 Molecule of the Month article).

Binding of calicheamicins, in contrast, involves interaction with two parts of the molecule. The ‘head’ of the molecule makes specific interactions with a TCCT sequence in the DNA (in the case of calicheamicin γ1), which is achieved from the minor groove (intercalation is not necessary) allowing the saccharide ‘tail’ to fit into the minor groove. (Ikemoto et al. 1995).

Drug–DNA interactions

(Constructed from 3D Structure images on the Protein Data Bank website)

Sequence specificity

A concern of the poster is the fact that the interaction of calicheamicin is sequence specific (there is apparently a preference for d(T-C-C-T).d(A-G-G-A)) whereas access to the bases is restricted in the minor groove. This is addressed in the paper by Ikemoto et al., but without illustration, assuming you are able to visualize the chemical interactions in your mind. I have used Jmol to view the structure 2PIK, have prepared a couple of screen shots to help illustrate the details I shall quote from the text of the paper. chemical structure of calicheamicin

Cleavage of the DNA is performed by the enediyne aglycone (R), which does not make contact with the bases. Two of the regions that do interact with bases are the thio-sugar ring (B) and the aromatic ring (C). These are shown below in the complex of calicheamicin (coloured yellow) with a deoxy-oligonucleotide duplex, together with a close-up of the interactions of these rings.

Interaction of calicheamicin with bases

In the left-hand frame the DNA has standard cpk colouring, and the phosphates (orange–red) lining the minor groove are evident. The base-pairs are perpendicular to the plane of the image. In the second frame I have tilted the image slightly to allow the rings of the bases to be seen, and coloured the bases (actually the whole nucleoside) red/white/green/blue for A/T/G/C. Quoting from the Ikemoto paper:

The thio sugar B is positioned edgewise in the minor groove and contacts the A20 residue through van der Waals and hydrogen bonding (B ring hydroxyl to N3 of the base) interactions. The aromatic ring C is positioned between the walls of the minor groove with its iodine and CH3 groups directed toward the floor of the minor groove.… The S-carbonyl linker, which adopts an orthogonal alignment relative to the plane of ring C (favored by the steric demands of the ortho aromatic ring substituents), bridges the minor groove and makes van der Waals contacts with the opposing walls of the groove.

This may not have the clarity of, say, Watson and Crick base-pairing, but neither does the interaction of proteins with particular DNA sequences — one needs to examine the multiple interactions that occur. What I think it does show is that this drug can make specific contact to bases, even though it binds in the minor groove.

| improve this answer | |
  • 3
    $\begingroup$ thank you a lot for your reply. however still I cannot fully understand..I thought that binding with minor groove is non-specific, in contrast with binding with major groove that is specific. So that's why I wondered since the binding is not specific and major groove is wider than minor, why calicheamicins act only in minor groove. thank you in advance! $\endgroup$ – marilu May 13 at 15:26
  • 1
    $\begingroup$ @marilu — Generalizations have their uses, but biology is full of exceptions, and if you are talking about interactions you are talking about individual chemistry. One needs a representation with drug and DNA in stick representation to see the interaction, although then the grooves are not obvious. Unfortunately the original paper does not have a suitable picture. I'll see what I can find and then flesh out my answer. May take a few days. $\endgroup$ – David May 13 at 17:28
  • $\begingroup$ thank you a lot! $\endgroup$ – marilu May 13 at 18:52
  • 1
    $\begingroup$ @marilu — That's the best I can do. If you need more detail you'll have to grapple with the paper yourself and get to grips with a molecular graphics program like Jmol. (It can be fun, but there is a learning curve.) $\endgroup$ – David May 17 at 17:34
  • $\begingroup$ I am so grateful!THANK you so much for your time and help!!!I get it now!:) $\endgroup$ – marilu May 17 at 19:01

Your Answer

By clicking “Post Your Answer”, you agree to our terms of service, privacy policy and cookie policy

Not the answer you're looking for? Browse other questions tagged or ask your own question.