Aromatic interactions in tryptophan-containing peptides: crystal structures of model tryptophan peptides and phenylalanine analogs.

The crystal structures of the peptides, Boc-Leu-Trp-Val-OMe (1), Ac-Leu-Trp-Val-OMe (2a and 2b), Boc-Leu-Phe-Val-OMe (3), Ac-Leu-Phe-Val-OMe (4), and Boc-Ala-Aib-Leu-Trp-Val-OMe (5) have been determined by X-ray diffraction in order to explore the nature of interactions between aromatic rings, specifically the indole side chain of Trp residues. Peptide 1 adopts a type I beta-turn conformation stabilized by an intramolecular 4-->1 hydrogen bond. Molecules of 1 pack into helical columns stabilized by two intermolecular hydrogen bonds, Leu(1)NH...O(2)Trp(2) and IndoleNH...O(1)Leu(1). The superhelical columns further pack into the tetragonal space group P4(3) by means of a continuous network of indole-indole interactions. Peptide 2 crystallizes in two polymorphic forms, P2(1) (2a) and P2(1)2(1)2(1) (2b). In both forms, the peptide backbone is extended, with antiparallel beta-sheet association being observed in crystals. Extended strand conformations and antiparallel beta-sheet formation are also observed in the Phe-containing analogs, Boc-Leu-Phe-Val-OMe (3) and Ac-Leu-Phe-Val-OMe (4). Peptide 5 forms a short stretch of 3(10)-helix. Analysis of aromatic-aromatic and aromatic-amide interactions in the structures of peptides, 1, 2a, 2b are reported along with the examples of 14 Trp-containing peptides from the Cambridge Crystallographic Database. The results suggest that there is no dramatic preference for a preferred orientation of two proximal indole rings. In Trp-containing peptides specific orientations of the indole ring, with respect to the preceding and succeeding peptide units, appear to be preferred in beta-turns and extended structures.     

三叶肽：从结构到功能

三叶结构域是一段由38－39个氨基酸组成的多肽序列,其中包含6个高度保守的半胱氨酸残基,这6个半胱氨酸残基以1－5,2－4,3－6的交联方式形成三对二硫,窝囊鑫肽链折叠成特征性的三叶结构。已发现的哺乳动物三叶肽有三种：pS1、SP及ITF。三叶肽通常位于消化道腔面的粘膜层,具有保护和修复功能,在维持粘膜的完整性中发挥着重要作用。     

Chloroplast transit peptides: structure, function and evolution

It is thought that two to three thousand different proteins are targeted to the chloroplast, and the 'transit peptides' that act as chloroplast targeting sequences are probably the largest class of targeting sequences in plants. At a primary structural level, transit peptide sequences are highly divergent in length, composition and organization. An emerging concept suggests that transit peptides contain multiple domains that provide either distinct or overlapping functions. These functions include direct interaction with envelope lipids, chloroplast receptors and the stromal processing peptidase. The genomic organization of transit peptides suggests that these domains might have originated from distinct exons, which were shuffled and streamlined throughout evolution to yield a modern, multifunctional transit peptide. Although still poorly characterized, this evolutionary process could yield transit peptides with different domain organizations. The plasticity of transit peptide design is consistent with the diverse biological functions of chloroplast proteins.     

Alpha-helical cationic antimicrobial peptides: relationships of structure and function

Antimicrobial peptides (AMPs), with their extraordinary properties, such as broad-spectrum activity, rapid action and difficult development of resistance, have become promising molecules as new antibiotics. Despite their various mechanisms of action, the interaction of AMPs with the bacterial cell membrane is the key step for their mode of action. Moreover, it is generally accepted that the membrane is the primary target of most AMPs, and the interaction between AMPs and eukaryotic cell membranes (causing toxicity to host cells) limits their clinical application. Therefore, researchers are engaged in reforming or de novo designing AMPs as a ‘single-edged sword’ that contains high antimicrobial activity yet low cytotoxicity against eukaryotic cells. To improve the antimicrobial activity of AMPs, the relationship between the structure and function of AMPs has been rigorously pursued. In this review, we focus on the current knowledge of α-helical cationic antimicrobial peptides, one of the most common types of AMPs in nature.     

EVH1 domains: structure, function and interactions

Drosophila enabled/vasodilator-stimulated phosphoprotein homology 1 (EVH1) domains are 115 residue protein-protein interaction modules which provide essential links for their host proteins to various signal transduction pathways. Many EVH1-containing proteins are associated closely with actin-based structures and are involved in re-organization of the actin cytoskeleton. EVH1 domains are also present in proteins enriched in neuronal tissue, thus implicating them as potential mediators of synaptic plasticity, linking them to memory formation and learning. Like Src homology 3, WW and GYF domains and profilin, EVH1 domains recognize and bind specific proline-rich sequences (PRSs). The binding is of low affinity, but tightly regulated by the high specificity encoded into residues in the protein:peptide interface. In general, a small (3-6 residue) 'core' PRS in the target protein binds a 'recognition pocket' on the domain surface. Further affinity- and specificity-increasing interactions are then formed between additional domain epitopes and peptide 'core-flanking' residues. The three-dimensional structures of EVH1:peptide complexes now reveal, in great detail, some of the most important features of these interactions and allow us to better understand the origins of specificity, ligand orientation and sequence degeneracy of target peptides, in low affinity signalling complexes.     

Stereochemistry of guanidine-metal interactions: implications for L-arginine-metal interactions in protein structure and function

The geometries of 150 guanidine-metal ion interactions retrieved from crystal structures deposited in the Cambridge Structural Database have been analyzed. Metal ions exhibit a preference for anti coordination stereochemistry in the plane of the unprotonated guanidine group, usually in chelate complexes with a diguanidine moiety, but syn-oriented interactions are occasionally found for single guanidine-metal interactions. Three L-arginine-metal coordination interactions are found in metalloenzyme structures deposited in the Protein Data Bank: biotin synthase from E. coli, His-67 --> Arg human carbonic anhydrase I, and inactivated B. caldovelox arginase complexed with L-arginine. In these proteins, L-arginine-metal coordination adopts syn/out-of-plane and anti/in-plane coordination stereochemistry. The implications of these results for L-arginine-metal interactions in protein structure and function are discussed. Although such interactions are rare, this analysis serves as a useful reference point for the growing interest in enzymes containing L-arginine residues that function as general bases or metal ligands.     

昆虫抗菌肽的结构和功能研究现状

昆虫抗菌肽是昆虫血淋巴中的一类活性肽。在昆虫感染病菌或体壁受到损伤的情况下其脂肪体能迅速合成一系列抗菌活性物质并释放到血淋巴中发挥作用,抑杀多种致病菌、真菌、病毒等,但不破坏生物体的正常细胞。对昆虫抗菌肽的结构特征、生物活性及抗菌肽分子的作用模式的最新研究进展作了综述。     

Intramolecular interactions at protein surfaces and their impact on protein function

Protein surfaces play a key role in the biological function of proteins. Consequently, structural features of protein surfaces are the basis for predicting function from structure. A well-established principle of binding by proteins is that ligands must compete with water and other small molecules to form interactions with protein surfaces. A less obvious issue, and the emphasis of this article, is that ligands must also compete with interactions among residues at protein surfaces. Results from structural surveys, a variety of experimental studies and computations suggest that intramolecular interactions are present at protein surfaces and that the energetics of these interactions can change when proteins bind to other molecules.     

Aromatic interactions in model systems

A thorough knowledge of noncovalent interactions is crucial to the understanding of biological complexity. One of the less well understood but significant weak interactions in nature is the aromatic interaction. Recent studies have provided new insight into the driving force, stability and selectivity of these interactions. The contribution of solvophobic and electrostatic interactions have been shown to be inextricably linked. Moreover, the influence of electrostatic and solvophobic components on the selectivity of aromatic interactions has been demonstrated.     

Faunal impact on vegetation structure and ecosystem function in mangrove forests: A review

The last 20 years witnessed a real paradigm shift concerning the impact of biotic factors on ecosystem functions as well as on vegetation structure of mangrove forests. Before this small scientific revolution took place, structural aspects of mangrove forests were viewed to be the result of abiotic processes acting from the bottom-up, while, at ecosystem level, the outwelling hypothesis stated that mangroves primary production was removed via tidal action and carried to adjacent nearshore ecosystems where it fuelled detrital based food-webs. The sesarmid crabs were the first macrofaunal taxon to be considered a main actor in mangrove structuring processes, thanks to a number of studies carried out in the Indo-Pacific forests in the late 1970s and early 1980s. Following these classical papers, a number of studies on Sesarmidae feeding and burrowing ecology were carried out, which leave no doubts about the great importance of these herbivorous crabs in structuring and functioning Old world ecosystems. Although Sesarmidae are still considered very important in shaping mangrove structure and functioning, recent literature emphasizes the significance of other invertebrates. The Ocypodidae have now been shown to have the same role as Sesarmidae in terms of retention of forest products and organic matter processing in New world mangroves. In both New and Old world mangroves, crabs process large amounts of algal primary production, contribute consistently to retention of mangrove production and as ecosystem engineers, change particle size distribution and enhance soil aeration. Our understanding of the strong impact of gastropods, by means of high intake rates of mangrove products and differential consumption of propagules, has changed only recently. The role of insects must also be stressed. It is now clear that older techniques used to assess herbivory rates by insects strongly underestimate their impact, both in case of leaf eating and wood boring species and that herbivorous insects can potentially play a strong role in many aspects of mangrove ecology. Moreover, researchers only recently realized that ant–plant interactions may form an important contribution to our understanding of insect–plant dynamics in these habitats. Ants seem to be able to relieve mangroves from important herbivores such as many insects and sesarmid crabs. It thus seems likely that ants have positive effects on mangrove performance.     

G proteins and G-protein-coupled receptors: structure, function and interactions.

The G protein family continues to grow and at least 15 heterotrimeric G proteins have now been identified. This review deals with the nature of the functional domains of the members of the G-protein-coupled receptor family as well as the associated G proteins.     

Protein interactions with platinum-DNA adducts: from structure to function

Because of the efficacy of cisplatin and carboplatin in a wide variety of chemotherapeutic regimens, hundreds of platinum(II) and platinum(IV) complexes have been synthesized and evaluated as anticancer agents over the past 30 years. Of the many third generation platinum compounds evaluated to date, only oxaliplatin has been approved for clinical usage in the United States. Thus, it is important to understand the mechanistic basis for the differences in efficacy, mutagenicity and tumor range between cisplatin and oxaliplatin. Cisplatin and oxaliplain form the same types of adducts at the same sites on DNA. The most abundant adduct for both compounds is the Pt-GG intrastrand diadduct. Cisplatin-GG adducts are preferentially recognized by mismatch repair proteins and some damage-recognition proteins, and this differential recognition of cisplatin- and oxaliplatin-GG adducts is thought to contribute to the differences in cytotoxicity and tumor range of cisplatin and oxaliplatin. A detailed kinetic analysis of the insertion and extension steps of dNTP incorporation in the vicinity of the adduct shows that both pol beta and pol eta catalyze translesion synthesis past oxaliplatin-GG adducts with greater efficiency than past cisplatin-GG adducts. In the case of pol eta, the efficiency and fidelity of translesion synthesis in vitro is very similar to that previously observed with cyclobutane TT dimers, suggesting that pol eta is likely to be involved in error-free bypass of Pt adducts in vivo. This has been confirmed for cisplatin by comparing the cisplatin-induced mutation frequency in human fibroblast cell lines with and without pol eta. Thus, the greater efficiency of bypass of oxaliplatin-GG adducts by pol eta is likely to explain the lower mutagenicity of oxaliplatin compared to cisplatin. The ability of these cellular proteins to discriminate between cisplatin and oxaliplatin adducts suggest that there exist significant conformational differences between the adducts, yet the crystal structures of the cisplatin- and oxaliplatin-GG adducts were very similar. We have recently solved the solution structure of the oxaliplatin-GG adduct and have shown that it is significantly different from the previously published solution structures of the cisplatin-GG adducts. Furthermore, the observed differences in conformation provide a logical explanation for the differential recognition of cisplatin and oxaliplatin adducts by mismatch repair and damage-recognition proteins. Molecular modeling studies are currently underway to analyze the mechanistic basis for the differential bypass of cisplatin and oxaliplatin adducts by DNA polymerases.     

Amphiphilic alpha-helical antimicrobial peptides and their structure/function relationships

To facilitate microbial membrane invasion, amphiphilic alpha-helical antimicrobial peptides (alpha-AMPs) show a spatial segregation of hydrophobic and hydrophilic residues about the alpha-helical long axis. Here we discuss potential mechanisms by which these peptides are able to disrupt membrane structure and the structural characteristics, which are required for function.     

Aromatic side-chain interactions in proteins: near- and far-sequence Tyr-X pairs

In the present study, an extensive analysis of the aromatic Tyr-X interactions is performed on a data set of 593 PDB structures, X being Phe, His, Tyr, and Trp. The nonredundant Tyr-X pairs (2645) were retained and separated by both the residue distance in the sequence and the secondary structures they bridge. Similar to the Phe-X and His-X pairs, the far-sequence Tyr-X pairs (X partner > five apart in the sequence: 74%) show comparable secondary structures and conformers for either type of X partner, in contrast with the near-sequence Tyr-X pairs (26%). As the Phe-X pairs, the near-sequence Tyr-X pairs stabilize secondary structures, mainly the alpha- helices (positions 1, 3, and 4) and the beta-strands (position 2). Like the Phe-X and His-X pairs, most far-sequence Tyr-X pairs (34%) bridge beta-strands and only 11% bridge helices. As for the Phe-X and the His-X pairs, the X partners of the far-sequence Tyr-X pairs are frequently "above" the tyrosine ring with tilted and normal rings, whereas the X partner of the near-sequence Tyr-X pairs gradually moves from the "aside" to the "above" location, together with a progressive decrease of normal and increase of parallel rings, respectively. Unlike the His-X pairs, the interactions of the hetroatom in Tyr-X pairs are only favored with a sequence position +4 and over, owing to the spatial accessibility of the heteroatom.     

Pathogenicity islands of virulent bacteria: structure, function and impact on microbial evolution

Virulence genes of pathogenic bacteria, which code for toxins, adhesins, invasins or other virulence factors, may be located on transmissible genetic elements such as transposons, plasmids or bacteriophages. In addition, such genes may be part of particular regions on the bacterial chromosome, termed‘pathogenicity islands’(Pais). Pathogenicity islands are found in Gram-negative as well as in Gram-positive bacteria. They are present in the genome of pathogenic strains of a given species but absent or only rarely present in those of non-pathogenic variants of the same or related species. They comprise large DNA regions (up to 200 kb of DNA) and often carry more than one virulence gene, the G+C contents of which often differ from those of the remaining bacterial genome. In most cases, Pais are flanked by specific DNA sequences, such as direct repeats or insertion sequence (IS) elements. In addition, Pais of certain bacteria (e.g. uropathogenic Escherichia coli, Yersinia spp., Helicobacter pylori) have the tendency to delete with high frequencies or may undergo duplications and amplifications. Pais are often associated with tRNA loci, which may represent target sites for the chromosomal integration of these elements. Bacteriophage attachment sites and cryptic genes on Pais, which are homologous to phage integrase genes, plasmid origins of replication or IS elements, indicate that these particular genetic elements were previously able to spread among bacterial populations by horizontal gene transfer, a process known to contribute to microbial evolution.     

Bacterial cyanogenesis: impact on biotic interactions

The ability of bacteria to influence organisms that they associate with via metabolite production is one of the hallmarks of microbial interactions. One metabolite of interest is the metabolic poison cyanide. Production of this metabolite is an unique characteristic of certain bacteria that inhabit a wide array of habitats ranging from the human body to the rhizosphere. This review focuses on four targets of cyanogenic bacteria: the human lung, plant pathogens, plants and invertebrates. For a number of cyanogenic bacteria, the contribution of cyanide to the interaction has been rigorously tested using mutants altered in cyanide production. Both deleterious and stimulatory effects of cyanogenic bacteria on other organisms have been documented. In addition, the HCN synthase‐encoding gene cluster hcnABC has served as a marker of cyanogenic capability in the soil environment revealing both genetic diversity at this locus and regulatory influences by other organisms. The pervasive nature of cyanogenesis in a number of different ecological contexts encourages exploration of this bacterial ability and its possible optimization for improving human health, crop production and pest control.     

Backbone side-chain interactions in peptides

IR, ¹H-NMR and X-ray experiments have been carried out on dipeptides with the Pro-Asp and Pro-Asn sequences protected on both ends by amide groups. The Pro-Asp dipeptide was investigated for the carboxylic, methyl ester and carboxylate forms of the Asp residue.In solution, all dipeptides are found to accommodate almost exclusively the I-turn conformation stabilized by an interaction between the Asp or Asn-NH and CO bonds. The I-turn percentage roughly parallels the basicity of the Asp or Asn side substituent, and decreases from Asp^- to Asn, and to Asp or Asp (OMe).The I-turn, stabilized by the interaction involving the Asp-CO site, is retained in the crystal structure of the Pro-Asp(OMe) dipeptide. The Pro-Asp and Pro-Asn dipeptides assume a II-turn conformation in the solid state and the polar Asp or Asn side-groups are involved in a complex network of intermolecular interactions.     

昆虫抗菌肽和抗真菌肽结构与功能的关系及分子设计

在对GenBank和EMBL数据库中登录的昆虫抗微生物肽 (antimicrobial peptide, AMP), 即昆虫抗菌肽 (antibacterial peptide) 和抗真菌肽 (antifungal peptide, AFP) 进行归类整理的基础上,对天蚕素族(cecropins )抗菌肽结构与功能的关系及人工改造的分子设计策略,特别是对目前新发现的一些昆虫抗真菌肽的已知结构与功能关系的研究进展、存在问题等进行了简要介绍和分析,为从事昆虫抗微生物肽的理论研究和发展新型抗生素药物提供了必要的信息。     

Lipid-protein interactions as determinants of membrane protein structure and function

To determine how the lipid environment affects membrane protein structure and function, strains of Escherichia coli were developed in which normal phospholipid composition can be altered or foreign lipids can be introduced. The properties of LacY (lactose permease) were investigated as a function of lipid environment. Assembly of LacY in membranes lacking PE (phosphatidylethanolamine) results in misorientation of the N-terminal six-TM (transmembrane domain) helical bundle with loss of energy-dependent uphill transport and retention of energy-independent downhill transport. Post-assembly introduction of PE results in nearly native orientation of TMs and restoration of uphill transport. Foreign lipids with no net charge can substitute for PE in supporting native LacY topology, but restoration of uphill transport is dependent on native topology and the proper folding of a solvent-exposed domain. Increasing the positive charge density of the cytoplasmically exposed surface of LacY counters TM misorientation in the absence of neutral lipids, demonstrating that charge interactions between these domains and the surface of the membrane bilayer are determinants of TM orientation. Therefore membrane protein organization or reorganization is determined either during initial assembly or post-insertionally through direct interactions between the protein and the lipid environment, which affects the topogenic potency of opposing charged residues as topological signals independent of the translocon.