authoritative, comprehensive and systematic

Directed enzyme evolution: beyond the low-hanging fruit

Molecular recognition and function of riboswitches

Going beyond five bases in DNA sequencing

Constructing structural networks of signaling pathways on the proteome scale

Membrane protein structure determination by electron crystallography

Structural insights into RNA recognition and activation of RIG-I-like receptors

The modular serine proteases of the complement cascade

Modeling nucleic acids

Electron crystallography — the waking beauty of structural biology

Cytokine receptor activation at the cell surface

Linking folding and binding

Many cellular proteins are intrinsically disordered and undergo folding, in whole or in part, upon binding to their physiological targets. The past few years have seen an exponential increase in papers describing characterization of intrinsically disordered proteins, both free and bound to targets. Although NMR spectroscopy remains the favored tool, a number of new biophysical techniques are proving exceptionally useful in defining the limits of the conformational ensembles. Advances have been…

Volume 19, Issue 1, 01 February 2009, Pp 31-38
Wright, P.E. | Dyson, H.J.

Protein folding studied by single-molecule FRET

A complete understanding of a protein-folding mechanism requires description of the distribution of microscopic pathways that connect the folded and unfolded states. This distribution can, in principle, be described by computer simulations and theoretical models of protein folding, but is hidden in conventional experiments on large ensembles of molecules because only average properties are measured. A long-term goal of single-molecule fluorescence studies is to time-resolve the structural…

Volume 18, Issue 1, 01 February 2008, Pp 16-26
Schuler, B. | Eaton, W.A.

Function and structure of inherently disordered proteins

The application of bioinformatics methodologies to proteins inherently lacking 3D structure has brought increased attention to these macromolecules. Here topics concerning these proteins are discussed, including their prediction from amino acid sequence, their enrichment in eukaryotes compared to prokaryotes, their more rapid evolution compared to structured proteins, their organization into specific groups, their structural preferences, their half-lives in cells, their contributions to…

Volume 18, Issue 6, 01 December 2008, Pp 756-764
Dunker, A.K. | Silman, I. | Uversky, V.N. | Sussman, J.L.

Structure and mechanism of ABC transporter proteins

ATP-binding cassette (ABC) transporters are ubiquitous membrane proteins that couple the transport of diverse substrates across cellular membranes to the hydrolysis of ATP. The crystal structures of four ABC transporters have recently been determined. They reveal similar arrangements of the conserved ATP-hydrolyzing nucleotide-binding domains, but unrelated architectures of the transmembrane domains, with the notable exception of a common 'coupling helix' that is essential for transmitting…

Volume 17, Issue 4, 01 August 2007, Pp 412-418
Hollenstein, K. | Dawson, R.J. | Locher, K.P.

Polymorphism in the intermediates and products of amyloid assembly

Amyloid formation reactions exhibit two classes of polymorphisms: the metastable intermediates commonly observed during amyloid formation and the range of conformationally distinct mature fibrils often seen at the reaction endpoint. Although recent data suggest that spherical oligomers and protofibrils in most cases are not obligate intermediates of amyloid assembly, oligomeric states might sometimes serve as on-pathway intermediates. Mature amyloid polymorphs self-propagate as a result of the…

Volume 17, Issue 1, 01 February 2007, Pp 48-57
Kodali, R. | Wetzel, R.

Atomic-level characterization of disordered protein ensembles

The roles of unfolded states of proteins in normal folding and in diseases involving aggregation, as well as the prevalence and regulatory functions of intrinsically disordered proteins, have become increasingly recognized. The structural representation of these disordered states as ensembles of interconverting conformers can therefore provide critical insights. Experimental methods can be used to probe ensemble-averaged structural properties of disordered states and computational approaches…

Volume 17, Issue 1, 01 February 2007, Pp 3-14
Mittag, T. | Forman-Kay, J.D.

The structural biology of HIV assembly

HIV assembly and replication proceed through the formation of morphologically distinct immature and mature viral capsids that are organized by the Gag polyprotein (immature) and by the fully processed CA protein (mature). The Gag polyprotein is composed of three folded polypeptides (MA, CA, and NC) and three smaller peptides (SP1, SP2, and p6) that function together to coordinate membrane binding and Gag-Gag lattice interactions in immature virions. Following budding, HIV maturation is…

Volume 18, Issue 2, 01 April 2008, Pp 203-217
Ganser-Pornillos, B.K. | Yeager, M. | Sundquist, W.I.

Long-timescale molecular dynamics simulations of protein structure and function

Molecular dynamics simulations allow for atomic-level characterization of biomolecular processes such as the conformational transitions associated with protein function. The computational demands of such simulations, however, have historically prevented them from reaching the microsecond and greater timescales on which these events often occur. Recent advances in algorithms, software, and computer hardware have made microsecond-timescale simulations with tens of thousands of atoms practical,…

Volume 19, Issue 2, 01 April 2009, Pp 120-127
Klepeis, J.L. | Lindorff-Larsen, K. | Dror, R.O. | Shaw, D.E.

Flexible ligand docking to multiple receptor conformations: a practical alternative

State of the art docking algorithms predict an incorrect binding pose for about 50-70% of all ligands when only a single fixed receptor conformation is considered. In many more cases, lack of receptor flexibility results in meaningless ligand binding scores, even when the correct pose is obtained. Incorporating conformational rearrangements of the receptor binding pocket into predictions of both ligand binding pose and binding score is crucial for improving structure-based drug design and…

Volume 18, Issue 2, 01 April 2008, Pp 178-184
Totrov, M. | Abagyan, R.

Multiscale modeling of biomolecular systems: in serial and in parallel

Considerable progress has been recently achieved in the multiscale modeling of complex biological processes. Multiscale models have now investigated the structure and dynamics of lipid membranes, proteins, peptides and DNA over length and time scales ranging from the atomic to the macroscopic. Serial multiscale methods that parameterize low-resolution coarse-grained models with data from high-resolution models have studied long time or length scale phenomena that cannot be investigated with…

Volume 17, Issue 2, 01 April 2007, Pp 192-198
Ayton, G.S. | Noid, W.G. | Voth, G.A.

The structures of quadruplex nucleic acids and their drug complexes

Quadruplex nucleic acids are four-stranded structures formed from short tracts of G-rich sequence associating together. Their formation from eukaryotic telomeric DNA sequences is well established, at least in vitro, and has more recently been the focus of attention as novel anticancer targets since their formation inhibits the telomerase complex from maintaining telomere length in cancer cells. Structural studies have revealed a diversity of topologies for telomeric quadruplexes, which are…

Volume 19, Issue 3, 01 June 2009, Pp 239-250
Neidle, S.

Progress and challenges in protein structure prediction

Depending on whether similar structures are found in the PDB library, the protein structure prediction can be categorized into template-based modeling and free modeling. Although threading is an efficient tool to detect the structural analogs, the advancements in methodology development have come to a steady state. Encouraging progress is observed in structure refinement which aims at drawing template structures closer to the native; this has been mainly driven by the use of multiple structure…

Volume 18, Issue 3, 01 June 2008, Pp 342-348
Zhang, Y.

RNA recognition motifs: boring? Not quite

The RNA recognition motif (RRM) is one of the most abundant protein domains in eukaryotes. While the structure of this domain is well characterized by the packing of two α-helices on a four-stranded β-sheet, the mode of protein and RNA recognition by RRMs is not clear owing to the high variability of these interactions. Here we report recent structural data on RRM-RNA and RRM-protein interactions showing the ability of this domain to modulate its binding affinity and specificity using each of…

Volume 18, Issue 3, 01 June 2008, Pp 290-298
Cléry, A. | Blatter, M. | Allain, F.H.-T.

Intrinsic dynamics of enzymes in the unbound state and relation to allosteric regulation

In recent years, there has been a surge in the number of studies exploring the relationship between proteins' equilibrium dynamics and structural changes involved in function. An emerging concept, supported by both theory and experiments, is that under native state conditions proteins have an intrinsic ability to sample conformations that meet functional requirements. A typical example is the ability of enzymes to sample open and closed forms, irrespective of substrate, succeeded by the…

Volume 17, Issue 6, 01 December 2007, Pp 633-640
Bahar, I. | Chennubhotla, C. | Tobi, D.

Recent advances in implicit solvent-based methods for biomolecular simulations

Implicit solvent-based methods play an increasingly important role in molecular modeling of biomolecular structure and dynamics. Recent methodological developments have mainly focused on the extension of the generalized Born (GB) formalism for variable dielectric environments and accurate treatment of nonpolar solvation. Extensive efforts in parameterization of GB models and implicit solvent force fields have enabled ab initio simulation of protein folding to native or near-native structures.…

Volume 18, Issue 2, 01 April 2008, Pp 140-148
Chen, J. | Brooks III, C.L. | Khandogin, J.

Functions of cell surface galectin-glycoprotein lattices

Programmed remodeling of cell surface glycans by the sequential action of specific glycosyltransferases can control biological processes by generating or masking ligands for endogenous lectins. Galectins, a family of animal lectins with affinity for β-galactosides, can form multivalent complexes with cell surface glycoconjugates and deliver a variety of intracellular signals to modulate cell activation, differentiation, and survival. Recent efforts involving genetic or biochemical manipulation…

Volume 17, Issue 5, 01 October 2007, Pp 513-520
Rabinovich, G.A. | Toscano, M.A. | Jackson, S.S. | Vasta, G.R.

Poly(dA:dT) tracts: major determinants of nucleosome organization

Homopolymeric stretches of deoxyadenosine nucleotides (A's) on one strand of double-stranded DNA, referred to as poly(dA:dT) tracts or A-tracts, are overabundant in eukaryotic genomes. They have unusual structural, dynamic, and mechanical properties, and may resist sharp bending. Such unusual material properties, together with their overabundance in eukaryotes, raised the possibility that poly(dA:dT) tracts might function in eukaryotes to influence the organization of nucleosomes at many…

Volume 19, Issue 1, 01 February 2009, Pp 65-71
Segal, E. | Widom, J.

The molecular architecture of protein-protein binding sites

The formation of specific protein interactions plays a crucial role in most, if not all, biological processes, including signal transduction, cell regulation, the immune response and others. Recent advances in our understanding of the molecular architecture of protein-protein binding sites, which facilitates such diversity in binding affinity and specificity, are enabling us to address key questions. What is the amino acid composition of binding sites? What are interface hotspots? How are…

Volume 17, Issue 1, 01 February 2007, Pp 67-76
Reichmann, D. | Rahat, O. | Cohen, M. | Neuvirth, H. | Schreiber, G.

RNA helicases - one fold for many functions

RNA helicases are a large group of enzymes that function in virtually all aspects of RNA metabolism. Although RNA helicases share a highly conserved structure, different enzymes display a wide array of biochemical activities, including RNA duplex unwinding, protein displacement from RNA and strand annealing. Recent structural and functional studies have started to illuminate the mechanisms by which this remarkable diversity of functions can be conducted by the conserved helicase fold. © 2007…

Volume 17, Issue 3, 01 June 2007, Pp 316-324
Jankowsky, E. | Fairman, M.E.

Membrane proteins: molecular dynamics simulations

Molecular dynamics simulations of membrane proteins are making rapid progress, because of new high-resolution structures, advances in computer hardware and atomistic simulation algorithms, and the recent introduction of coarse-grained models for membranes and proteins. In addition to several large ion channel simulations, recent studies have explored how individual amino acids interact with the bilayer or snorkel/anchor to the headgroup region, and it has been possible to calculate…

Volume 18, Issue 4, 01 August 2008, Pp 425-431
Lindahl, E. | Sansom, M.S.

Sialic acids as regulators of molecular and cellular interactions

The wide occurrence of sialic acids (Sia) in various chemical forms linked as monomers or polymers in an outstanding position in a multitude of complex carbohydrates of animals and microorganisms renders them as most versatile function modulators in cell biology and pathology. A survey is presented of recent advances in the study of the influences that Sias have as bulky hydrophilic and electronegatively charged monosaccharides on animal cells and on their interaction with microorganisms. Some…

Volume 19, Issue 5, 01 October 2009, Pp 507-514
Schauer, R.

Biophysical characterization of intrinsically disordered proteins

The challenges associated with the structural characterization of disordered proteins have resulted in the application of a host of biophysical methods to such systems. NMR spectroscopy is perhaps the most readily suited technique for providing high-resolution structural information on disordered protein states in solution. Optical methods, solid state NMR, ESR and X-ray scattering can also provide valuable information regarding the ensemble of conformations sampled by disordered states.…

Volume 19, Issue 1, 01 February 2009, Pp 23-30
Eliezer, D.

Structural basis of viral invasion: lessons from paramyxovirus F

The structures of glycoproteins that mediate enveloped virus entry into cells have revealed dramatic structural changes that accompany membrane fusion and provided mechanistic insights into this process. The group of class I viral fusion proteins includes the influenza hemagglutinin, paramyxovirus F, HIV env, and other mechanistically related fusogens, but these proteins are unrelated in sequence and exhibit clearly distinct structural features. Recently determined crystal structures of the…

Volume 17, Issue 4, 01 August 2007, Pp 427-436
Lamb, R.A. | Jardetzky, T.S.

Chaperone machines in action

How do chaperones operate in cells? For some major chaperones it is clear what they do, though mostly not how they do it. Hsp60, 70 and 100 families carry out folding, unfolding or disaggregation of proteins. Regarding mechanisms of action, we have the clearest picture of the ATP-driven mechanism of the bacterial Hsp60s, and structures of full-length Hsp70 and 90 family members are beginning to give insights into their allosteric mechanisms. Recent advances are giving an improved understanding…

Volume 18, Issue 1, 01 February 2008, Pp 35-42
Saibil, H.R.

Transition networks for modeling the kinetics of conformational change in macromolecules

The kinetics and thermodynamics of complex transitions in biomolecules can be modeled in terms of a network of transitions between the relevant conformational substates. Such a transition network, which overcomes the fundamental limitations of reaction-coordinate-based methods, can be constructed either based on the features of the energy landscape, or from molecular dynamics simulations. Energy-landscape-based networks are generated with the aid of automated path-optimization methods, and,…

Volume 18, Issue 2, 01 April 2008, Pp 154-162
Noé, F. | Fischer, S.

Proteome folding and aggregation

Direct measurement of protein binding energetics by isothermal titration calorimetry

Recent advances in single molecule studies of nucleosomes

Zinc finger proteins: new insights into structural and functional diversity

Coarse-grained molecular simulations of large biomolecules

Structure and mechanism of ABC transporter proteins

Structural insights into agonist-induced activation of G-protein-coupled receptors

The leucine-rich repeat as a protein recognition motif

Linking structural change with functional regulation—insights from mass spectrometry

Mechanisms and principles of N-linked protein glycosylation