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We data-mined the Protein Data Bank for short intrahelical deformations, including π bulges. These are defined as a contiguous stretch of intrahelical residues deviating from the standard α-helical i->i-4 hydrogen bonding pattern, bilaterally flanked by at least one α-helical turn resulting in a helix kink of less than 40 o . We find that such motifs exist in 4.7% of a PDB subset filtered...
Two recent studies on DNA topoisomerases combine the power of biochemistry and structural biology to gain new insight at the atomic level into how these enzymes interact with DNA (Perry and Mondragon, 2003 [Structure, Nov. 2003]; [this issue]).
We present a computational algorithm that can be used to analyze the generic mechanisms involved in protein-DNA recognition. Our approach is based on energy calculations for the full set of base sequences that can be threaded onto the DNA within a protein-DNA complex. It is able to reproduce experimental consensus binding sequences for a variety of DNA binding proteins and also correlates well with...
Many surface proteins of Gram-positive bacteria, which play important roles during the pathogenesis of human infections, are anchored to the cell wall envelope by a mechanism requiring sortases. Sortase B, a cysteine transpeptidase from Staphylococcus aureus, cleaves the C-terminal sorting signal of IsdC at the NPQTN motif and tethers the polypeptide to the pentaglycine cell wall cross-bridge. During...
Superantigens are a class of microbial proteins with the ability to excessively activate T cells by binding to the T cell receptor. The staphylococcal and streptococcal superantigens are closely related in structure and possess an N-terminal domain that resembles an OB fold and a C-terminal domain similar to a β-grasp fold. Yersinia pseudotuberculosis produces superantigens, YPMa, YPMb, and YPMc,...
In this issue of Structure, three crystal structures of staphylococcal sortase B reveal a new active site for cysteine proteases, which requires a Cys-Arg catalytic dyad for substrate turnover.
Human thymidine phosphorylase (HTP), also known as platelet-derived endothelial cell growth factor (PD-ECGF), is overexpressed in certain solid tumors where it is linked to poor prognosis. HTP expression is utilized for certain chemotherapeutic strategies and is also thought to play a role in tumor angiogenesis. We determined the structure of HTP bound to the small molecule inhibitor 5-chloro-6-[1-(2-iminopyrrolidinyl)...
The first model of the cooperative DNA binding of two important regulatory proteins, CAP and lac repressor, seamlessly unites atomistic and continuum descriptions of biomolecules and suggests variable DNA loop winding in response to protein binding.
The cyclotides are a family of disulfide-rich proteins from plants. They have the characteristic structural features of a circular protein backbone and a knotted arrangement of disulfide bonds. Structural and biochemical studies of the cyclotides suggest that their unique physiological stability can be loaned to bioactive peptide fragments for pharmaceutical and agricultural development. In particular,...
dUTPase is an essential enzyme involved with nucleotide metabolism and replication. We report here the X-ray structure of Trypanosoma cruzi dUTPase in its native conformation and as a complex with dUDP. These reveal a novel protein fold that displays no structural similarities to previously described dUTPases. The molecular unit is a dimer with two active sites. Nucleotide binding promotes extensive...
Cells can switch the functional states of extracellular matrix proteins by stretching them while exerting mechanical force. Using steered molecular dynamics, we investigated how the mechanical stability of FnIII modules from the cell adhesion protein fibronectin is affected by natural variations in their amino acid sequences. Despite remarkably similar tertiary structures, FnIII modules share low...
Vaccinia topoisomerase IB forms a covalent DNA-(3'-phosphotyrosyl)-enzyme intermediate at its target site 5'-CCCTTp↓ in duplex DNA. The contributions of backbone electrostatics and individual phosphate oxygens to the transesterification reaction were probed by introducing 22 single Rp and Sp methylphosphonate diastereomers at 11 positions flanking the cleavage site. Methyl groups at eight positions...
Water transport channels in membrane proteins of the aquaporin superfamily are impermeable to ions, including H + and OH - . We examine the molecular basis for the blockage of proton translocation through the single-file water chain in the pore of a bacterial aquaporin, GlpF. We compute the reversible thermodynamic work for the two complementary steps of the Grotthuss ''hop-and-turn''...
In this issue of Structure, the crystal structure of trypanosomal dUTPase exemplifies convergent evolution and the role of induced fit in substrate recognition. This structure opens the door for developing antiparasitic therapies that induce cell death by targeting a dUTPase.
The crystal structure of TATA binding protein (TBP) from a mesothermophilic archaeon, Sulfolobus acidocaldarius, has been determined at a resolution of 2.0 A with an R factor of 20.9%. By comparing this structure with the structures of TBPs from a hyperthermophilic archaeon and mesophilic eukaryotes, as well as by comparing amino acid sequences of TBPs from archaea, covering a wide range of optimum...
The experimentally derived mechanical hierarchy of the different FnIII domains from fibronectin is well predicted here by Steered Molecular Dynamics simulations. In addition, the critical hydrogen bond model proposed might explain the behavior of these domains under different chemical conditions.
PTP-BL is a large phosphatase that is implicated in cellular processes as diverse as cytokinesis, actin-cytoskeletal rearrangement, and apoptosis. Five PDZ domains mediate its cellular role by binding to the C termini of target proteins, forming multiprotein complexes. The second PDZ domain (PDZ2) binds to the C termini of the tumor suppressor protein APC and the LIM domain-containing protein RIL;...
Enzyme-substrate complexes of phosphomannomutase/phosphoglucomutase (PMM/PGM) reveal the structural basis of the enzyme's ability to use four different substrates in catalysis. High-resolution structures with glucose 1-phosphate, glucose 6-phosphate, mannose 1-phosphate, and mannose 6-phosphate show that the position of the phosphate group of each substrate is held constant by a conserved network...
The structure of the catalytic and electron-transfer subunits (NarGH) of the integral membrane protein, respiratory nitrate reductase (Nar) has been determined to 2.0 A resolution revealing the molecular architecture of this Mo-bisMGD (molybdopterin-guanine-dinucleotide) containing enzyme which includes a previously undetected FeS cluster. Nar, together with the related enzyme formate dehydrogenase...
Catabolite gene activator protein (CAP) and lac repressor (LR) are celebrated transcription-regulating proteins that bind to DNA cooperatively forming a ternary complex with the promoter loop. Here we present a multiscale model of the ternary complex derived from crystal structures of the proteins and a continuous structure of the DNA loop built using the theory of elasticity. We predict that the...
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