The pore dimensions of gramicidin A

Smart, Oliver S.; Goodfellow, Julia M.; Wallace, B.A.

doi:10.1016/s0006-3495(93)81293-1

Cited by 608 publications

(575 citation statements)

References 37 publications

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“…The geometry analysis of the final model with Procheck 38 gave statistics of 97.5% and 2.5% for the most favored and additional allowed regions, respectively, on the Ramachandran plot. The pore radius of the ion conduction pathway was analyzed using the program HOLE 39 and the electrostatic potentials were calculated using the program APBS 40 . All structure figures were prepared with Pymol 41 .…”

Section: Methodsmentioning

confidence: 99%

The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture

Lee

Guo

Zeng

et al. 2017

Nature

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TMEM175 is a lysosomal K+ channel important for maintaining the lysosomal membrane potential and pH stability1. It contains two homologous copies of a six-transmembrane (6-TM) domain, which has no sequence homology to the canonical tetrameric K+ channels and lacks the TVGYG selectivity filter motif2–4. Present in a subset of bacteria and archaea, the prokaryotic TMEM175 contains only a single 6-TM domain and functions as a tetramer. Here, we present the crystal structure of a prokaryotic TMEM175 from Chamaesiphon minutus, CmTMEM175, whose architecture represents a completely different fold from that of canonical K+ channels. All six transmembrane helices of CmTMEM175 are tightly packed within each subunit without undergoing domain swap. The highly conserved TM1 acts as the pore lining inner helix, creating an hour-glass shaped ion permeation pathway in the channel tetramer. Three layers of hydrophobic residues on the C-terminal half of TM1s form a bottle neck along the ion conduction pathway and serve as the selectivity filter of the channel. Mutagenesis analysis suggests that the first layer of the highly conserved isoleucine residues in the filter plays the central role in channel selectivity. Thus, the structure of CmTMEM175 represents a novel architecture of a tetrameric cation channel whose ion selectivity mechanism appears distinct from that of the classical K+ channel family.

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Section: Methodsmentioning

confidence: 99%

The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture

Lee

Guo

Zeng

et al. 2017

Nature

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“…Pore cross-sectional areas and pore radii were measured from the crystal structures using HOLE2, which determines the largest sphere that fits in the channel space without overlapping the van der Waals surfaces of surrounding residues (15). Superposition of structures was done in Coot.…”

Section: Methodsmentioning

confidence: 99%

Structural context shapes the aquaporin selectivity filter

Savage

O’Connell

Miercke

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Aquaporins are transmembrane channels that facilitate the permeation of water and small, uncharged amphipathic molecules across cellular membranes. One distinct aquaporin subfamily contains pure water channels, whereas a second subfamily contains channels that conduct small alditols such as glycerol, in addition to water. Distinction between these substrates is central to aquaporin function, though the contributions of protein structural motifs required for selectivity are not yet fully characterized. To address this question, we sequentially engineered three signature amino acids of the glycerol-conducting subfamily into the Escherichia coli water channel aquaporin Z (AqpZ). Functional analysis of these mutant channels showed a decrease in water permeability but not the expected increase in glycerol conduction. Using X-ray crystallography, we determined the atomic resolution structures of the mutant channels. The structures revealed a channel surprisingly similar in size to the wild-type AqpZ pore. Comparison with measured rates of transport showed that, as the size of the selectivity filter region of the channel approaches that of water, channel hydrophilicity dominated water conduction energetics. In contrast, the major determinant of selectivity for larger amphipathic molecules such as glycerol was channel cross-section size. Finally, we find that, although the selectivity filter region is indeed central to substrate transport, other structural elements that do not directly interact with the substrates, such as the loop connecting helices M6 and M7, and the C loop between helices C4 and C5, play an essential role in facilitating selectivity.mutagenesis | transmembrane protein | X-ray structure A quaporins (AQPs) are integral membrane channels found throughout all kingdoms of life that selectively facilitate the permeation of water and small amphipathic solutes across cellular membranes (1). They display rates of conduction near the diffusion limit, but are remarkably selective and exclude all ions, including hydroxide and hydronium. AQPs are functionally divided into two subfamilies, the orthodox AQPs, which are selective for water and the more promiscuous aquaglyceroporins (AQGPs), which conduct both water and amphipathic solutes such as glycerol. This selectivity is central to biological function, and AQPs are involved in such disparate functions as water reabsorption in the kidney, glycerol efflux from adipocytes, and glycerol uptake by the causative agent of malaria, Plasmodium falciparum (1, 2). The Escherichia coli genome encodes one member of each subfamily, aquaporin Z (AqpZ) (3), an orthodox AQP, and the glycerol facilitator (GlpF) (4), an AQGP.Atomic resolution X-ray structures of both AQPs and AQGPs have been determined and a comparison of these structures reveals the conserved structural architecture characteristic of the family and particular motifs that modulate function (5-7). All members are tetramers of four functional monomeric channels. The structure of the GlpF monomer (Fig. 1) is a right...

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“…Research toward this end includes analytical area and volume calculation (Connolly, 1983;Richmond, 1984;Gibson & Scheraga, 1987); cavity identification and measurement (Rashin et al, 1986;Voorintholt et al, 1989;Ho & Marshall, 1990;Alard & Wodak, 1991;Nicholls et al, 1993;Smart et al, 1993;Hubbard et al, 1994;Kleywegt & Jones, 1994;Williams et al, 1994); pocket or cleft computation (Kuntz et al, 1982;Delaney, 1992;Levitt & Banaszak, 1992;Laskowski, 1995;Peters et al, 1996); and molecular shape representation (Lin et al, 1994). Although useful, their application to pocket calculations is limited by lack of fully automatic computations, lack of analytical measurements of area and volume with real physical meaning, and/or use of arbitrarily adjusted parameters.…”

Section: Pocket and Cavity Analysismentioning

confidence: 99%

Anatomy of protein pockets and cavities: Measurement of binding site geometry and implications for ligand design

1998

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Identification and size characterization of surface pockets and occluded cavities are initial steps in protein structurebased ligand design. A new program, CAST, for automatically locating and measuring protein pockets and cavities, is based on precise computational geometry methods, including alpha shape and discrete flow theory. CAST identifies and measures pockets and pocket mouth openings, as well as cavities. The program specifies the atoms lining pockets, pocket openings, and buried cavities; the volume and area of pockets and cavities; and the area and circumference of mouth openings. CAST analysis of over 100 proteins has been carried out; proteins examined include a set of SI monomeric enzyme-ligand structures, several elastase-inhibitor complexes, the pockets and cavities in protein crystal structures and quantifying their size. The method is a computational geometry treatment of complex shapes, based on alpha shape and discrete flow theory, and a related suite of programs,

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The pore dimensions of gramicidin A

Cited by 608 publications

References 37 publications

The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture

The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture

Structural context shapes the aquaporin selectivity filter

Anatomy of protein pockets and cavities: Measurement of binding site geometry and implications for ligand design

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