Last modified 12th April '95 © Birkbeck College 1995

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All-Alpha Topologies

With MAGE installed, study this Kinemage

The Lone Helix

There are a number of examples of small proteins (or peptides) which consist of little more than a single helix. A striking example is gif glucagon, a hormone involved in regulating sugar metabolism in mammals (as does insulin).

The Helix-turn-helix motif

Different variations of this supersecondary structure have been introduced in a previous chapter . The simplest packing arrangement of a domain of two helices is for them to lie antiparallel, connected by a short loop. This constitutes the structure of the small (63 residue) RNA-binding protein Rop , which is found in certain plasmids (small circular molecules of double-stranded DNA occurring in bacteria and yeast) and involved in their replication. There is a slight twist in the arrangement as shown.

The Four-helix Bundle

The four-helix bundle is found in a number of different proteins. In many cases the helices part of a single polypeptide chain, connected to each other by three loops. However, the Rop molecule is in fact a dimer of two of the two-helix units shown above.

In four-helix-bundle proteins the interfaces between the helices consist mostly of hydrophobic residues while polar side chains on the exposed surfaces interact with the aqueous environment, as indicated below:

Compare this with the arrangement of residues that would be expected in a membrane-spanning helical domain, which has previously been indicated. The central helices of the photosynthetic reaction centre in fact are arranged similar to the four- helix bundle.

Other examples exhibit a much more open packing arrangement, as in the steroid-binding proteins uteroglobin, and Clara cell 17kDa protein (gif, pdb)


The four helices may be arranged in a simple up-and-down topology, as indicated.
Click here for a diagram of myohemerythrin, which has this fold (others are cytochrome c', cytochrome b-562, which have two molecules in the asymmetric unit).

A more complex arrangement is possible:
Click here for the four-helix bundle topology of ferritin.

The ligand-binding sites of these proteins occur between the alpha helices. The ligands can be seen by selecting the structures listed above and choosing the Display:sticks and Colour:chain options, e.g. below is a diagram of cytochrome C' indicating the haem group, which is sited between the first and fourth helices.


A number of cytokines consist of four alpha helices in a bundle. Click here for a diagram of Interleukin-2, human Growth Hormone, Granulocyte-macrophage colony-stimulating factor (GM-CSF) and Interleukin-4, by Manuel Peitsch of Glaxo Geneva. Also examine Simon Brocklehurst's page on cytokines.

Alpha domains which bind DNA

Transcription factors are proteins which bind to control regions of DNA. These regions are "upstream" of the structural gene (the sequence which actually codes for a protein) whose transcription they regulate. Transcription factors have a DNA-binding domain and a domain that activates transcription.

The RNA-binding two-helix protein Rop has already been mentioned. A three-helix bundle forms the basis of a DNA-binding domain which occurs in a number of proteins- for example homeodomain proteins. Examine the crystal structure of engrailed homeodomain binding to DNA, and three different diagrams courtesy of Manuel Peitsch.

Click here for the structure of the cro repressor from phage 434.

Also refer to the GCN4 transcription factor leucine zipper described in Antti Iivanainen's section on coiled coils.


The globin fold usually consists of eight alpha helices (e.g. myoglobin). The two helices at the end of the chain are antiparallel, forming a helix-turn-helix motif, but the remainder of the fold does not include any characterized supersecondary structures. These helices pack against each other with larger angles, around 50 °, between them than occurs between antiparallel helices (approximately 20°). See the section below on helix-helix packing. Jane Richardson (1981) describes the globin fold as a "Greek key helix bundle", due to the topological similarity with the Greek key arrangement of antiparallel beta-sheets (see section on all beta topologies).

In all, fifty-six categories of "mostly alpha" folds are listed in the Structural Classification of Proteins database. A number of the entries have links to appropriate diagrams by Manuel Peitsch. The CATH Protein Structure Classification Database" at UCL lists 9 orthogonal, and 3 aligned topologies of "Mainly Alpha" structures.

Helix-helix packing

When alpha-helices pack against each other, the side-chains in their interface are buried. The two interface areas should have complementary surfaces. The surface of an alpha-helix can be thought of as consisting of grooves and ridges, like a screw thread : for instance, the side chains of every 4th residue form a ridge (because there are 3.6 residues per turn). The direction of this ridge is 26° from the direction of the helix axis. Therefore if 2 helices pack such that such a ridge from each fits into the other's groove, the expected angle between the two is 52°. In fact, in the distribution of this angle between packed alpha-helices, there is a sharp peak at 50°. Besides the type of ridge described, ridges can be formed by other staggerings of residues, such as every 3rd residue, or indeed every residue. Which ridges are used for packing depends on the size and conformations of the side chains at these relative positions. The "i+4" ridge is believed to be the most common because residues at every 4th position have side-chains which are more closely aligned than in "i+3" or "i+1" ridges as indicated below.

Again, refer to Chothia (1984)

Two other types of packing do occur, however : between an "i+4" ridge and an "i+3" ridge (there is an angle of 23° between the 2 helix axes) and between an "i+4" and an "i+1" ridge (the helices are 105° apart). The "ridges and grooves" model does not describe all the helix-helix packings, as there are examples with unusual interaxial angles. For instance in the globin fold a pair of helices (B and E) pack such that their ridges cross each other, by means of a notch formed at a pair of glycine residues.

Click here for a diagram of the notch in the ridges of helices B and H, and click here for a slice through a space-filling model of the two helices packing against each other.

The interaxial distance between packed helices varies from 6.8-12.0Å, the mean being 9.4 Å;the mean interpenetration of atoms at the interface is 2.3Å. Therefore it is mainly side chains which make the contacts between the helices.

Other Distinctive All-alpha proteins include :-

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J. Walshaw & Alan Mills