Dn-symmetrical tertiary templates for the design of tubular proteins11Edited by J. Thornton

North, Benjamin; Summa, Christopher M.; Ghirlanda, Giovanna; DeGrado, William F.

doi:10.1006/jmbi.2001.4900

Cited by 50 publications

(58 citation statements)

References 38 publications

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“…The target protein was a mathematically created (idealized) homotrimeric parallel coiled-coil protein having C 3 symmetry, a superhelical pitch of 120 Å, and (initially) 27 residues per helix (36). Similar structures have been observed in prototypical threestranded coiled coils (37)(38)(39).…”

Section: Resultsmentioning

confidence: 91%

Computational design of a protein crystal

Lanci

MacDermaid

Kang

et al. 2012

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

158

165

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Protein crystals have catalytic and materials applications and are central to efforts in structural biology and therapeutic development. Designing predetermined crystal structures can be subtle given the complexity of proteins and the noncovalent interactions that govern crystallization. De novo protein design provides an approach to engineer highly complex nanoscale molecular structures, and often the positions of atoms can be programmed with sub-Å precision. Herein, a computational approach is presented for the design of proteins that self-assemble in three dimensions to yield macroscopic crystals. A three-helix coiled-coil protein is designed de novo to form a polar, layered, three-dimensional crystal having the P6 space group, which has a "honeycomb-like" structure and hexameric channels that span the crystal. The approach involves: (i) creating an ensemble of crystalline structures consistent with the targeted symmetry; (ii) characterizing this ensemble to identify "designable" structures from minima in the sequencestructure energy landscape and designing sequences for these structures; (iii) experimentally characterizing candidate proteins. A 2.1 Å resolution X-ray crystal structure of one such designed protein exhibits sub-Å agreement [backbone root mean square deviation (rmsd)] with the computational model of the crystal. This approach to crystal design has potential applications to the de novo design of nanostructured materials and to the modification of natural proteins to facilitate X-ray crystallographic analysis.M olecular design provides powerful tools for exploring how molecular properties dictate macroscopic structure and function. One of the most precise forms of self-organization, crystallization achieves orientation and symmetry across many length scales and can be leveraged to engineer materials with well-defined molecular order (1). In addition to their central role in structure determination, molecular crystals have many applications, including nanoparticle templating (2, 3), nonlinear optical devices (4), molecular scaffolding (5), and porous frameworks (6). A predictive understanding of how to achieve self-assembled macroscale structure and desired properties remains challenging, however, particularly when large, conformationally flexible molecules are employed.Small synthetic molecules have been designed that display complementary functional groups in a manner consistent with a chosen crystal structure. Intermolecular contacts are often patterned using strong, directional interactions (e.g., hydrogen bonding, metalcoordination, and electrostatic interactions) (7). The constituent molecules, however, are typically small and synthetic, thus limiting size, shape, and functionality. Hence, simultaneously achieving functional properties and the presentation of complementary intermolecular interactions that confer a targeted crystal structure can be difficult. Commonly, weak intermolecular forces stabilize crystalline ordering, and as a result, quantitative, predictive approaches to crystal de...

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Section: Resultsmentioning

confidence: 91%

Computational design of a protein crystal

Lanci

MacDermaid

Kang

et al. 2012

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

158

165

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“…The idealized interhelical crossing angles (⍀) for the right-handed and left-handed crossing angles can be calculated from the geometry of the ␣-helix by using Eq. 1 (23,26,31):…”

Section: Methodsmentioning

confidence: 99%

Helix-packing motifs in membrane proteins

Walters¹,

DeGrado

2006

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

259

279

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The fold of a helical membrane protein is largely determined by interactions between membrane-imbedded helices. To elucidate recurring helix-helix interaction motifs, we dissected the crystallographic structures of membrane proteins into a library of interacting helical pairs. The pairs were clustered according to their three-dimensional similarity (rmsd <1.5 Å), allowing 90% of the library to be assigned to clusters consisting of at least five members. Surprisingly, three quarters of the helical pairs belong to one of five tightly clustered motifs whose structural features can be understood in terms of simple principles of helix-helix packing. Thus, the universe of common transmembrane helix-pairing motifs is relatively simple. The largest cluster, which comprises 29% of the library members, consists of an antiparallel motif with left-handed packing angles, and it is frequently stabilized by packing of small side chains occurring every seven residues in the sequence. Righthanded parallel and antiparallel structures show a similar tendency to segregate small residues to the helix-helix interface but spaced at four-residue intervals. Position-specific sequence propensities were derived for the most populated motifs. These structural and sequential motifs should be quite useful for the design and structural prediction of membrane proteins.helix-helix packing ͉ protein design ͉ structure prediction H elical transmembrane (TM) proteins are a major class of membrane proteins that are critically involved in functionally rich processes, including bioenergetics, signal transduction, ion transmission, and catalysis. The mechanisms by which TM proteins fold into native structures are beginning to be understood from a confluence of structural and biochemical studies (1-3). The determinants of a membrane protein's fold can be understood by dissecting its structure into pairs of interacting helices, which, together with the connecting loops and extramembrane domains, comprise the overall structure. Along these lines, various workers have examined the geometric characteristics of helix-helix interactions in membrane proteins (4) as well as the features in the amino acid sequences that predispose the helices to adopt these geometries. One outstanding success has been the recognition of the GX 3 G motif, in which Gly (or other small residues) spaced four residues apart mediate a close approach of TM helices (5-7). This motif was first observed in the TM domain of glycophorin A (GpA) (5) and has subsequently been found in both water-soluble (8) and membrane proteins (9). In the classical GpA GX 3 G motif, the helices cross with a right-handed crossing angle of Ϸ40°. In a different TM motif stabilized by ''knobs-into-holes'' packing (10), the helices cross with a smaller left-handed crossing angle.Other surveys of helix-helix packing in membrane proteins have focused on distributions of the interhelical angles, distances, and the composition of the side chains packed at the interface. The helix-helix interfaces tend to be well pa...

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“…TM bundles were also constructed using coiled ␣-helices based on Crick's equations (32,33) with the following parameters kept constant: (a) superhelical pitch set at 194 Å; (b) rise per residue of the minor helix set to 1.5 Å; (c) radius of the minor helix set at 2.25 Å; (d) periodicity of the minor helix set to 2/3.5; and (e) periodicity of the major helix set to 2/(pitch/ rise per residue). The superhelical radius was varied between 8.5 and 10.5 Å using a step size of 0.2 Å.…”

Section: Methodsmentioning

confidence: 99%

Identification of the Pore-lining Residues of the BM2 Ion Channel Protein of Influenza B Virus

Soto

Ohigashi

et al. 2008

Journal of Biological Chemistry

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The influenza B virus BM2 proton-selective ion channel is essential for virus uncoating, a process that occurs in the acidic environment of the endosome. The BM2 channel causes acidification of the interior of the virus particle, which results in dissociation of the viral membrane protein from the ribonucleoprotein core. The BM2 protein is similar to the A/M2 protein ion channel of influenza A virus (A/M2) in that it contains an HXXXW motif. Unlike the A/M2 protein, the BM2 protein is not inhibited by the antiviral drug amantadine. We used mutagenesis to ascertain the pore-lining residues of the BM2 ion channel. The specific activity (relative to wild type), reversal voltage, and susceptibility to modification by (2-aminoethyl)-methane thiosulfonate and N-ethylmaleimide of cysteine mutant proteins were measured in oocytes. . Based on these experimental data, a BM2 transmembrane domain model is proposed. The presence of polar residues in the pore is a probable explanation for the amantadine insensitivity of the BM2 protein and suggests that related but more polar compounds might serve as useful inhibitors of the protein.

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Dn-symmetrical tertiary templates for the design of tubular proteins11Edited by J. Thornton

Cited by 50 publications

References 38 publications

Computational design of a protein crystal

Computational design of a protein crystal

Helix-packing motifs in membrane proteins

Identification of the Pore-lining Residues of the BM2 Ion Channel Protein of Influenza B Virus

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