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The Structure of the Potassium Channel

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The Structure of the Potassium Channel RESEARCH ARTICLES The Structure of the Potassium Potassium Channel Architecture 1 The amino acid sequence of the K1 chan- nel from Streptomyces lividans (KcsA K1 Channel: Molecular Basis of K channel) (5) is similar to that of other K1 channels, including vertebrate and inverte- Conduction and Selectivity brate voltage-dependent K1 channels, ver- tebrate inward rectifier and Ca21-activated Declan A. Doyle, Joa˜ o Morais Cabral, Richard A. Pfuetzner, K1 channels, K1 channels from plants and Anling Kuo, Jacqueline M. Gulbis, Steven L. Cohen, bacteria, and cyclic nucleotide-gated cation Brian T. Chait, Roderick MacKinnon* channels (Fig. 1). On the basis of hydro- phobicity analysis, there are two closely related varieties of K1 channels, those con- The potassium channel from Streptomyces lividans is an integral membrane protein with taining two membrane-spanning segments sequence similarity to all known K1 channels, particularly in the pore region. X-ray per subunit and those containing six. In all analysis with data to 3.2 angstroms reveals that four identical subunits create an inverted cases, the functional K1 channel protein is teepee, or cone, cradling the selectivity filter of the pore in its outer end. The narrow a tetramer (6), typically of four identical selectivity filter is only 12 angstroms long, whereas the remainder of the pore is wider subunits (7). Subunits of the two mem- and lined with hydrophobic amino acids. A large water-filled cavity and helix dipoles are brane-spanning variety appear to be short- positioned so as to overcome electrostatic destabilization of an ion in the pore at the ened versions of their larger counterparts, as center of the bilayer. Main chain carbonyl oxygen atoms from the K1 channel signature if they simply lack the first four membrane- sequence line the selectivity filter, which is held open by structural constraints to co- spanning segments. Although the KcsA K1 ordinate K1 ions but not smaller Na1 ions. The selectivity filter contains two K1 ions about channel is a two membrane-spanning K1 7.5 angstroms apart. This configuration promotes ion conduction by exploiting electro- channel, its amino acid sequence is actually static repulsive forces to overcome attractive forces between K1 ions and the selectivity closer to those of eukaryotic six membrane- filter. The architecture of the pore establishes the physical principles underlying selective spanning K1 channels. In particular, its K1 conduction. sequence in the pore region, located be- tween the membrane-spanning stretches and containing the K1 channel signature sequence, is nearly identical to that found Potassium ions diffuse rapidly across cell properties, K1 channels are classified in the Drosophila (Shaker) and vertebrate membranes through proteins called K1 as “long pore channels,” invoking the voltage-gated K1 channels (Fig. 1). In an channels. This movement underlies many notion that multiple ions queue inside a accompanying paper, through a study of the fundamental biological processes, includ- long, narrow pore in single file. In KcsA K1 channel interaction with eukary- ing electrical signaling in the nervous sys- addition, the pores of all K1 channels otic K1 channel toxins, we confirm that tem. Potassium channels use diverse can be blocked by tetraethylammonium the KcsA pore structure is indeed very sim- mechanisms of gating (the processes by (TEA) ions (3). ilar to that of eukaryotic K1 channels and which the pore opens and closes), but they Molecular cloning and mutagenesis ex- that its structure is maintained when it is all exhibit very similar ion permeability periments have reinforced the conclusion removed from the membrane with deter- characteristics (1). All K1 channels show that all K1 channels have essentially the gent (8). a selectivity sequence of K1 ' Rb1 . same pore constitution. Without exception, We have determined the KcsA K1 Cs1, whereas permeability for the smallest all contain a critical amino acid sequence, channel structure from residue position 23 alkali metal ions Na1 and Li1 is immea- the K1 channel signature sequence. Muta- to 119 by x-ray crystallography (Table 1). surably low. Potassium is at least 10,000 tion of these amino acids disrupts the chan- The cytoplasmic carboxyl terminus (resi- times more permeant than Na1, a feature nel’s ability to discriminate between K1 dues 126 to 158) was removed in the prep- that is essential to the function of K1 and Na1 ions (4). aration and the remaining residues were channels. Potassium channels also share a Two aspects of ion conduction by K1 disordered. The KcsA K1 channel crystals constellation of permeability characteris- channels have tantalized biophysicists for are radiation-sensitive and the diffraction tics that is indicative of a multi-ion the past quarter century. First, what is the pattern is anisotropic, with reflections ob- conduction mechanism: The flux of ions chemical basis of the impressive fidelity served along the best and worst directions in one direction shows high-order cou- with which the channel distinguishes be- at 2.5 Å and 3.5 Å Bragg spacings, respec- pling to flux in the opposite direction, and tween K1 and Na1 ions, which are feature- tively. By data selection, anisotropy correc- ionic mixtures result in anomalous con- less spheres of Pauling radius 1.33 Å and tion, introduction of heavy atom sites by duction behavior (2). Because of these 0.95 Å, respectively? Second, how can K1 site-directed mutagenesis, averaging, and channels be so highly selective and at the solvent flattening, an interpretable electron D. A. Doyle, R. A. Pfuetzner, A. Kuo, and R. MacKinnon are in the Laboratory of Molecular Neurobiology and Bio- same time, apparently paradoxically, exhib- density map was calculated (Fig. 2, A physics and the Howard Hughes Medical Institute, Rock- it a throughput rate approaching the diffu- through C). This map was without main efeller University, 1230 York Avenue, New York, NY sion limit? The 104 margin by which K1 is chain breaks and showed strong side chain 10021, USA. J. M. Cabral and J. M. Gulbis are in the selected over Na1 implies strong energetic density (Fig. 2C). The model was refined Laboratory of Molecular Neurobiology and Biophysics, 1 Rockefeller University, 1230 York Avenue, New York, NY interactions between K ions and the pore. with data to 3.2 Å (the data set was 93 % 10021, USA. S. L. Cohen and B. T. Chait are in the And yet strong energetic interactions seem complete to 3.2 Å with 67% completeness Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, Rockefeller University, 1230 York Avenue, incongruent with throughput rates up to between 3.3 Å and 3.2 Å), maintaining 8 New York, NY 10021, USA. 10 ions per second. How can these two highly restrained stereochemistry and keep- 1 *To whom correspondence should be addressed. E-mail: essential features of the K channel pore be ing tight noncrystallographic symmetry re- [email protected] reconciled? straints. The refinement procedure was www.sciencemag.org z SCIENCE z VOL. 280 z 3 APRIL 1998 69 monitored by minimizing the value R-free brane normal by about 25° and are slightly the pore region and the inner helix. Even (29.0%) and its separation from R-crystal- kinked, so that the subunits open like the Na1 and Ca21 channels show distant relat- lographic (28.0%). The presence of four petals of a flower facing the outside of the edness over these segments. The teepee ar- molecules (subunits) in the asymmetric unit cell. The open petals house the structure chitecture of the K1 channel pore likely of the crystal provides a very significant formed by the pore region near the extra- will be a general feature of all of these enhancement of the accuracy of the crys- cellular surface of the membrane. This re- cation channels, with four inner helices tallographic analysis; first, by enabling av- gion contains the K1 channel signature arranged like the poles of a teepee, four pore eraging of the electron density over four sequence, which forms the selectivity filter helices, and a selectivity filter—tuned to crystallographically independent regions of (4). The essential features of subunit pack- select the appropriate cation—located close the multiple isomorphous replacement ing can be appreciated by viewing the rela- to the extracellular surface. (MIR) map, and second, by providing a tion between the four inner helices and the This structure of the KcsA K1 channel powerful set of constraints on the atomic four pore helices (Fig. 3D). The four inner is in excellent agreement with results from model during refinement (9). helices pack against each other as a bundle functional and mutagenesis studies on Shak- The K1 channel is a tetramer with four- near the intracellular aspect of the mem- er and other eukaryotic K1 channels (Fig. fold symmetry about a central pore (Fig. 3, brane, giving the appearance of an inverted 4). The pore-region of K1 channels was A and B). Like several other membrane teepee. The pore helices are slotted in be- first defined with pore-blocking scorpion proteins, it has two layers of aromatic amino tween the poles of the teepee and are di- toxins (11). These inhibitors interact with acids positioned to extend into the lipid rected, with an amino-to-carboxyl sense, amino acids (Fig. 4, white) comprising the bilayer, presumably near the membrane-wa- toward a point near the center of the chan- broad extracellular-facing entryway to the ter interfaces (Fig. 3C) (10). Each subunit nel (Fig. 3, A, B, and D). This pore helix pore (12). The impermeant organic cation has two transmembrane a-helices connect- arrangement provides many of the intersub- TEA blocks K1 channels from both sides of ed by the roughly 30 amino acid pore re- unit contacts that hold the tetramer togeth- the membrane at distinct sites (13).
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