enantio selectivity obtained was so low as to be practically useless7–9. Gold and copper are from the same family of elements, and might there-fore be expected to exhibit similar catalytic behaviour. So why are gold catalysts so much better at chiral induction in these systems?

The gold ions — known as gold(I) ions — used in gold catalysts1 differ from most other metal centres because usually only two mol-ecules can bind to them at once; most metals can accommodate four or six molecules. Dur-ing catalysis, the gold ion binds to the reaction substrate and to another ligand, with the two molecules arranged as far apart as possible on opposite sides of the metal (Fig. 1b). In tran-sition-metal catalysis, good chiral induction occurs only when the ligand and the substrate are close together on the metal. But on gold(I) ions the bound molecules are so far apart that only low enantioselectivity can generally be obtained.

Toste and colleagues’ catalysts overcome this problem by using a counter-ion to induce chi-rality. The authors’ spectroscopic studies1 indi-cate that the cationic gold complex associates closely with the counter-ion in solution, as a result of charge interactions. As long as solvent molecules do not interfere, the chiral counter-ion can occupy the free space between the ligand and the substrate (Fig. 1b). The counter-ion thus probably ends up close to the substrate and so can induce chirality during the reac-tion. This is similar to a previously reported effect10 in which two independent ligand units cooperate to induce excellent chiral control in transition-metal-catalysed reactions.

The coming months will show how far this concept can be extended to other metals, but there will undoubtedly be difficulties to over-come. For example, because other metals can bind to more ligands than gold(I) ions, this will make it more difficult for a counter-ion to approach the metal centre and occupy a defined position close to the substrate. Nevertheless, the simple conditions developed by Toste and

Figure 1 | Chiral counter-ions in gold catalysis. Chiral compounds can exist as one of two mirror-image forms (enantiomers). Certain catalysts can control which of these enantiomers forms during a reaction. a, In reactions such as the one shown at the top, Toste and colleagues1 find that a cationic gold complex (blue), which ordinarily does not induce chirality, can promote the formation of a desired enantiomer in the presence of a

chiral counter-ion (green). b, During catalysis, reaction substrates and ligand molecules bind to gold (Au) cations on opposite sides of the metal, so the ligands are too distant to induce chirality on the substrate. The authors propose1 that counter-ions associate with the gold complex by charge attraction. This brings them close enough to the substrate to control the enantiomeric outcome of the reaction.

•NHSO2 Mes

O

R

R

OP

O

O

Catalyst NH

NHMesO2SSO2Mes

Majorenantiomer

Combined yield 97%Ratio 98:2

+

Benzene, 23 °C, 48 h

a b

Catalyst

Mes =

H3C CH3

CH3

Ligand Substrate

Counter-ion

Large distance

Shortdistance

Minorenantiomer

Ph(CH3)2PAu

–

Au

+

+

–

R =

colleagues1 should allow a broad range of coun-ter-ions and ligands to be screened rapidly. Perhaps a catalytic revolution is just around the corner. ■

A. Stephen K. Hashmi is at the Organisch-Chemisches Institut, Universität Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany.e-mail: hashmi@hashmi.de

1. Hamilton, G. L., Kang, E. J., Mba, M. & Toste, F. D. Science 317, 496–499 (2007).

STRUCTURAL BIOLOGY

Unexpected openingCecilia M. Canessa

Cell membranes contain channels that open to allow ions into cells. The structure of a sodium ion channel helps explain how it opens in response to protons, and settles a long-standing debate about its composition.

What do humans have in common with worms, flies, hydra and sea urchins? One answer is that they all have proteins known as degenerins1 that form pores in cell membranes for the passage of sodium ions. The acid-sens-ing ion channels (ASICs) belong to this family of proteins. They have been found in all verte-brates examined to date; even organisms with rudimentary nervous systems express at least one kind of ASIC. On page 316 of this issue, Gouaux and colleagues2 report the first crystal structure of one of these intriguing proteins. The structure turns out to be unlike that of any other known ion channel, and provides some surprising answers to questions about the shape and behaviour of ASICs.

Degenerins all share certain structural fea-tures: two regions (TM1 and TM2) that cross the cell membrane; short terminal sections that face the cytoplasm; and a large domain that lies

outside the cell. Although their constituent amino-acid sequence varies between different degenerins, the extracellular section always contains cysteine amino acids at certain posi-tions. Furthermore, the amino-acid sequence of TM2 — an essential component of the pore through which the ions pass — is remark-ably similar in all degenerins. The evolution-ary conservation of the TM2 structure makes these channels highly selective for sodium ions. Indeed, they have the highest sodium selectivity of all known ion channels, with a ratio of greater than 100:1 for sodium over potassium.

But the similarities between degenerins end there, as these ion channels have highly diverse functions and means of activation. Channels of the ASIC1 subclass found in the neurons of higher vertebrates open in response to extracellular hydrogen ions (protons, H+)3. The degenerins MEC-4 and MEC-10 in the

2. Hashmi, A. S. K. & Hutchings, G. J. Angew. Chem. Int. Edn 45, 7896–7936 (2006).

3. Hashmi, A. S. K. Chem. Rev. 107, 3180–3211 (2007).4. Ito, Y., Sawamura, M. & Hayashi, T. J. Am. Chem. Soc. 108,

6405–6406 (1986).5. Teles, J. H. et al. Angew. Chem. Int. Edn 37, 1415–1418 (1998).6. Mayer, S. & List, B. Angew. Chem. Int. Edn 45, 4193–4195

(2006).7. Llewellyn, D. B. & Arndtsen, B. A. Tetrahedron: Asym. 16,

1789–1799 (2005).8. Llewellyn, D. B. et al. Org. Lett. 26, 4165–4168 (2000).9. Lacour, J. & Hebbe-Viton, V. Chem. Soc. Rev. 32, 373–382

(2003).10. Reetz, M. T. et al. Angew. Chem. Int. Edn 42, 790–793 (2003).

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worm Caenorhabditis elegans are mechano-transducers — slight mechanical stimulation of the worm’s body surface induces a current in touch-responsive sensory neurons, an effect that is absent in animals lacking the mec-4 and mec-10 genes (ref. 4). Neurons in the garden snail Helix aspersa express a degenerin that is the only ion channel directly ‘gated’ by a peptide5. At the other end of the activation spectrum is ENaC (ref. 6), a sodium channel found in organs that regulate body sodium (such as the kidney, lung and the ducts of sweat glands). ENaC does not require a specific stim-ulus to open, but is constantly active.

A host of ions, toxins, small molecules, and enzymes and other proteins has been reported to bind to the extracellular domains of degener-ins to modulate these channels’ activities. Cati-ons with two positive charges — particularly calcium ions (Ca2+) — are crucial in this respect, because they stabilize a conformation of ASICs that makes the channels sensitive to protons.

Gouaux and colleagues2 now provide the first three-dimensional structure of one of these functionally eclectic ion channels. They report the structure of chicken ASIC1 in the ‘desen-sitized’ state. This is a conformation adopted by the channel after it has opened, when it has ceased to conduct ions because the pore has closed up again, even though protons remain bound to the extracellular domain. Many of the observed structural features support previous experimental results, but the authors report several remarkable findings.

Perhaps one of the most unexpected discov-eries is the number of subunits forming the channel. Previously, there were two schools of thought, one favouring four subunits and the other nine. Gouaux and colleagues’ structure settles the matter once and for all: there are three. This means that all the other proteins in the degenerin family also have three subunits. In ASIC1, these subunits are of all the same type, but ENaC is known to have three differ-ent kinds of subunit; it can therefore now be concluded that ENaC is a heterotrimer.

The overall shape of the extracellular domain

Figure 1 | Proposed mechanism for sodium-ion channel opening. Gouaux and colleagues2 report the crystal structure of the chicken ASIC1 protein, which forms a channel across cell membranes. The channel opens in response to hydrogen ions (protons, H+), so allowing sodium ions into cells. The authors propose the following mechanism. a, Protons bind to a cleft next to a thumb-shaped region (green) of the extracellular part of the protein. b, The proton-binding slightly displaces the thumb, which causes a conformational change that opens the channel.

a b

H+

is also surprising. It was expected to have a fun-nel shape that would concentrate sodium ions around the mouth of the pore, but in fact its rather compact mass provides no direct passage for ions. The only access points for sodium ions entering the pore are small windows formed by short loops that tether the extracellular domain to the transmembrane regions. As previously predicted, two transmembrane helices, mostly in TM2, line the pore itself.

The structure also shows that, in the desensi-tized state, the pore collapses without any ions trapped inside. This finding agrees with the notion that the pores of degenerins are narrow and able to hold only one ion at a time. Such narrow pores would strip water molecules from sodium ions before the ions enter the channel; the pores’ narrow shape would also account for the relatively low flow of ions through the channels, and for the fact that the channels select small metal ions — so sodium ions are preferred over the larger potassium ions.

The most intriguing part of ASIC1 is its large extracellular region — its size, ‘stickiness’ for other molecules and crucial role in channel opening have attracted much attention. Nev-ertheless, attempts to understand the gating mechanism of degenerin channels have been

frustrated by the paucity of structural informa-tion about the extracellular domain. Gouaux and colleagues’ structure2 provides some much-needed data. The authors identify a cluster of negatively charged amino-acid residues that form the proton sensor; these residues are brought together from distant parts of the protein by an appropriate fold.

Gouaux and colleagues propose that bind-ing of protons to the sensor displaces a thumb-shaped region of the protein; this nudges a short loop that connects the bulk of the extra-cellular domain to the transmembrane helices, so opening the pore (Fig. 1). This conforma-tional-switch mechanism might not apply to every degenerin because not all of them respond to protons, even though a proton sensor is present. It is therefore reasonable to assume that the proton sensor is necessary, but not sufficient, to elicit conformational changes extending beyond the thumb region.

Thanks to Gouaux and colleagues’ channel structure2, these and other hypotheses can now be tested experimentally. It might also be pos-sible to discover how the different channels can be gated by such diverse stimuli despite shar-ing a fundamentally common structure. The next task is to obtain the crystal structure of a channel in the open state, where sodium ions are found in the selectivity filter of the pore. This is an even greater technical challenge, but is essential if we are to observe the different conformations of the extracellular domain and so further elucidate the gating mechanism of these ubiquitous ion channels. ■

Cecilia M. Canessa is in the Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.e-mail: cecilia.canessa@yale.edu 1. Kellenberger, S. & Schild, L. Physiol. Rev. 82, 735–767 (2002).2. Jasti, J., Furukawa, H., Gonzales, E. B. & Gouaux, E. Nature

449, 316–322 (2007).3. Waldmann, R., Champigny, G., Bassilana, F., Heurteaux, C.

& Lazdunski, M. Nature 386, 173–177 (1997).4. Chelur, D. S. et al. Nature 420, 669–673 (2002).5. Lingueglia, E., Champigny, G., Lazdunski, M. & Barbry, P.

Nature 378, 730–733 (1995).6. Canessa, C. M. et al. Nature 367, 463–467 (1994).

GEOCHEMISTRY

Earth holds its breathChris J. Ballentine

Some inert-gas isotopes in Earth’s atmosphere can only have come from deep inside the planet. We thought we knew how much gas Earth gives up, and how it does it — but a challenge has emerged to the prevailing model.

Slowly, Earth is cooling. The culprit is solid convection, which transports hot, buoyant material to Earth’s surface from as far down as the core–mantle boundary, 2,900 kilometres beneath us. When this material reaches the

surface, some of it melts, and ‘incompatible’ ele-ments that are of the wrong size, or the wrong ionic charge, to fit into the remaining solid mineral crystal diffuse into the molten rock. These elements become highly concentrated in

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