Protein Data Bank
The Protein Data Bank is a database for the three-dimensional structural data of large biological molecules, such as proteins and nucleic acids. The data obtained by X-ray crystallography, NMR spectroscopy, or cryo-electron microscopy, submitted by biologists and biochemists from around the world, are accessible on the Internet via the websites of its member organisations; the PDB is overseen by an organization called the Worldwide Protein Data Bank, wwPDB. The PDB is a key in areas such as structural genomics. Most major scientific journals, some funding agencies, now require scientists to submit their structure data to the PDB. Many other databases use protein structures deposited in the PDB. For example, SCOP and CATH classify protein structures, while PDBsum provides a graphic overview of PDB entries using information from other sources, such as Gene ontology. Two forces converged to initiate the PDB: 1) a small but growing collection of sets of protein structure data determined by X-ray diffraction.
In 1969, with the sponsorship of Walter Hamilton at the Brookhaven National Laboratory, Edgar Meyer began to write software to store atomic coordinate files in a common format to make them available for geometric and graphical evaluation. By 1971, one of Meyer's programs, SEARCH, enabled researchers to remotely access information from the database to study protein structures offline. SEARCH was instrumental in enabling networking, thus marking the functional beginning of the PDB; the Protein Data Bank was announced in October 1971 in Nature New Biology as a joint venture between Cambridge Crystallographic Data Centre, UK and Brookhaven National Laboratory, USA. Upon Hamilton's death in 1973, Tom Koeztle took over direction of the PDB for the subsequent 20 years. In January 1994, Joel Sussman of Israel's Weizmann Institute of Science was appointed head of the PDB. In October 1998, the PDB was transferred to the Research Collaboratory for Structural Bioinformatics; the new director was Helen M. Berman of Rutgers University.
In 2003, with the formation of the wwPDB, the PDB became an international organization. The founding members are PDBe, RCSB, PDBj; the BMRB joined in 2006. Each of the four members of wwPDB can act as deposition, data processing and distribution centers for PDB data; the data processing refers to the fact that annotate each submitted entry. The data are automatically checked for plausibility; the PDB database is updated weekly. The PDB holdings list is updated weekly; as of 17 October 2018, the breakdown of current holdings is as follows: 120,052 structures in the PDB have a structure factor file. 9,734 structures have an NMR restraint file. 3,486 structures in the PDB have a chemical shifts file. 2,531 structures in the PDB have a 3DEM map file deposited in EM Data BankThese data show that most structures are determined by X-ray diffraction, but about 10% of structures are now determined by protein NMR. When using X-ray diffraction, approximations of the coordinates of the atoms of the protein are obtained, whereas estimations of the distances between pairs of atoms of the protein are found through NMR experiments.
Therefore, the final conformation of the protein is obtained, in the latter case, by solving a distance geometry problem. A few proteins are determined by cryo-electron microscopy; the significance of the structure factor files, mentioned above, is that, for PDB structures determined by X-ray diffraction that have a structure file, the electron density map may be viewed. The data of such structures is stored on the "electron density server". In the past, the number of structures in the PDB has grown at an exponential rate, passing the 100 registered structures milestone in 1982, the 1,000 in 1993, the 10,000 in 1999, the 100,000 in 2014. However, since 2007, the rate of accumulation of new protein structures appears to have plateaued; the file format used by the PDB was called the PDB file format. This original format was restricted by the width of computer punch cards to 80 characters per line. Around 1996, the "macromolecular Crystallographic Information file" format, mmCIF, an extension of the CIF format started to be phased in.
MmCIF is now the master format for the PDB archive. An XML version of this format, called PDBML, was described in 2005; the structure files can be downloaded in any of these three formats. In fact, individual files are downloaded into graphics packages using web addresses: For PDB format files, use, e.g. http://www.pdb.org/pdb/files/4hhb.pdb.gz or http://pdbe.org/download/4hhb For PDBML files, use, e.g. http://www.pdb.org/pdb/files/4hhb.xml.gz or http://pdbe.org/pdbml/4hhbThe "4hhb" is the PDB identifier. Each structure published in PDB receives a four-character alphanumeric identifier, its PDB ID; the structure files may be viewed using one of several free and open source computer programs, including Jmol, Pymol, VMD, Rasmol. Other non-free, shareware programs
Protein–protein interactions are the physical contacts of high specificity established between two or more protein molecules as a result of biochemical events steered by electrostatic forces including the hydrophobic effect. Many are physical contacts with molecular associations between chains that occur in a cell or in a living organism in a specific biomolecular context. Proteins act alone as their functions tend to be regulated. Many molecular processes within a cell are carried out by molecular machines that are built from a large number of protein components organized by their PPIs; these interactions make up the so-called interactomics of the organism, while aberrant PPIs are the basis of multiple aggregation-related diseases, such as Creutzfeldt–Jakob, Alzheimer's diseases, may lead to cancer. PPIs have been studied from different perspectives: biochemistry, quantum chemistry, molecular dynamics, signal transduction, among others. All this information enables the creation of large protein interaction networks – similar to metabolic or genetic/epigenetic networks – that empower the current knowledge on biochemical cascades and molecular etiology of disease, as well as the discovery of putative protein targets of therapeutic interest.
In many metabolic reactions, a protein that acts as an electron carrier binds to an enzyme that acts its reductase. After it receives an electron, it dissociates and binds to the next enzyme that acts its oxidase; these interactions between proteins are dependent on specific binding between proteins to ensure efficient electron transfer. Examples: mitochondrial oxidative phosphorylation chain system components cytochrome c-reductase / cytochrome c / cytochrome c oxidase. In the case of the mitochondrial P450 systems, the specific residues involved in the binding of the electron transfer protein adrenodoxin to its reductase were identified as two basic Arg residues on the surface of the reductase and two acidic Asp residues on the adrenodoxin. More recent work on the phylogeny of the reductase has shown that these residues involved in protein-protein interactions have been conserved throughout the evolution of this enzyme; the activity of the cell is regulated by extracellular signals. Signal propagation inside and/or along the interior of cells depends on PPIs between the various signaling molecules.
The recruitment of signaling pathways through PPIs is called signal transduction and plays a fundamental role in many biological processes and in many diseases including Parkinson's disease and cancer. A protein may be carrying another protein. In many biosynthetic processes enzymes interact with each other to produce small compounds or other macromolecules. Physiology of muscle contraction involves several interactions. Myosin filaments act by binding to actin enables filament sliding. Furthermore, members of the skeletal muscle lipid droplet-associated proteins family associate with other proteins, as activator of adipose triglyceride lipase and its coactivator comparative gene identification-58, to regulate lipolysis in skeletal muscle. To describe the types of protein–protein interactions it is important to consider that proteins can interact in a "transient" way or to interact with other proteins in a "stable" way to build multiprotein complexes that are molecular machines within the living systems.
A protein complex assembly can result in the formation of homo-oligomeric or hetero-oligomeric complexes. In addition to the conventional complexes, as enzyme-inhibitor and antibody-antigen, interactions can be established between domain-domain and domain-peptide. Another important distinction to identify protein-protein interactions is the way they have been determined, since there are techniques that measure direct physical interactions between protein pairs, named “binary” methods, while there are other techniques that measure physical interactions among groups of proteins, without pairwise determination of protein partners, named “co-complex” methods. Homo-oligomers are macromolecular complexes. Protein subunits assembly is guided by the establishment of non-covalent interactions in the quaternary structure of the protein. Disruption of homo-oligomers in order to return to the initial individual monomers requires denaturation of the complex. Several enzymes, carrier proteins, scaffolding proteins, transcriptional regulatory factors carry out their functions as homo-oligomers.
Distinct protein subunits interact in hetero-oligomers, which are essential to control several cellular functions. The importance of the communication between heterologous proteins is more evident during cell signaling events and such interactions are only possible due to structural domains within the proteins. Stable interactions involve proteins that interact for a long time, taking part of permanent complexes as subunits, in order to carry out structural or functional roles; these are the case of homo-oligomers, some hetero-oligomeric proteins, as the subunits of ATPase. On the other hand, a protein may interact and in a reversible manner with other proteins in only certain cellular contexts – cell type, cell cycle stage, external factors, presence of other binding proteins, etc. – as it happens with most of the proteins involved in biochemical cascades. These are called transient interactions. For example, some G protein-coupled receptors only transiently bind to Gi/o proteins when they are activated by extracellular ligands, while some Gq-coupled receptors, such as muscari
Innate immune system
The innate immune system is one of the two main immunity strategies found in vertebrates. The innate immune system is an older evolutionary defense strategy speaking, it is the dominant immune system response found in plants, fungi and primitive multicellular organisms; the major functions of the vertebrate innate immune system include: Recruiting immune cells to sites of infection through the production of chemical factors, including specialized chemical mediators called cytokines Activation of the complement cascade to identify bacteria, activate cells, promote clearance of antibody complexes or dead cells Identification and removal of foreign substances present in organs, tissues and lymph, by specialized white blood cells Activation of the adaptive immune system through a process known as antigen presentation Acting as a physical and chemical barrier to infectious agents. Anatomical barriers include physical and biological barriers; the epithelial surfaces form a physical barrier, impermeable to most infectious agents, acting as the first line of defense against invading organisms.
Desquamation of skin epithelium helps remove bacteria and other infectious agents that have adhered to the epithelial surfaces. Lack of blood vessels and inability of the epidermis to retain moisture, presence of sebaceous glands in the dermis provides an environment unsuitable for the survival of microbes. In the gastrointestinal and respiratory tract, movement due to peristalsis or cilia helps remove infectious agents. Mucus traps infectious agents; the gut flora can prevent the colonization of pathogenic bacteria by secreting toxic substances or by competing with pathogenic bacteria for nutrients or attachment to cell surfaces. The flushing action of tears and saliva helps prevent infection of mouth. Inflammation is one of the first responses of the immune system to irritation. Inflammation is stimulated by chemical factors released by injured cells and serves to establish a physical barrier against the spread of infection, to promote healing of any damaged tissue following the clearance of pathogens.
The process of acute inflammation is initiated by cells present in all tissues resident macrophages, dendritic cells, Kupffer cells, mast cells. These cells present receptors contained on the surface or within the cell, named pattern recognition receptors, which recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns. At the onset of an infection, burn, or other injuries, these cells undergo activation and release inflammatory mediators responsible for the clinical signs of inflammation. Chemical factors produced during inflammation sensitize pain receptors, cause local vasodilation of the blood vessels, attract phagocytes neutrophils. Neutrophils trigger other parts of the immune system by releasing factors that summon additional leukocytes and lymphocytes. Cytokines produced by macrophages and other cells of the innate immune system mediate the inflammatory response; these cytokines include TNF, HMGB1, IL-1.
The inflammatory response is characterized by the following symptoms: redness of the skin, due to locally increased blood circulation. The complement system is a biochemical cascade of the immune system that helps, or “complements”, the ability of antibodies to clear pathogens or mark them for destruction by other cells; the cascade is composed of many plasma proteins, synthesized in the liver by hepatocytes. The proteins work together to: trigger the recruitment of inflammatory cells "tag" pathogens for destruction by other cells by opsonizing, or coating, the surface of the pathogen form holes in the plasma membrane of the pathogen, resulting in cytolysis of the pathogen cell, causing the death of the pathogen rid the body of neutralised antigen-antibody complexes. There are three different complement systems: Classical, Lectin Classical: starts when antibody bind to bacteria Alternative: starts "spontaneously" Lectin: starts when lectins bind to mannose on bacteriaElements of the complement cascade can be found in many non-mammalian species including plants, birds and some species of invertebrates.
All white blood cells are known as leukocytes. Leukocytes differ from other cells of the body in that they are not associated with a particular organ or tissue. Leukocytes are able to move and interact with and capture cellular debris, foreign particles, invading m
Enzymes are macromolecular biological catalysts. Enzymes accelerate chemical reactions; the molecules upon which enzymes may act are called substrates and the enzyme converts the substrates into different molecules known as products. All metabolic processes in the cell need enzyme catalysis in order to occur at rates fast enough to sustain life. Metabolic pathways depend upon enzymes to catalyze individual steps; the study of enzymes is called enzymology and a new field of pseudoenzyme analysis has grown up, recognising that during evolution, some enzymes have lost the ability to carry out biological catalysis, reflected in their amino acid sequences and unusual'pseudocatalytic' properties. Enzymes are known to catalyze more than 5,000 biochemical reaction types. Most enzymes are proteins; the latter are called ribozymes. Enzymes' specificity comes from their unique three-dimensional structures. Like all catalysts, enzymes increase the reaction rate by lowering its activation energy; some enzymes can make their conversion of substrate to product occur many millions of times faster.
An extreme example is orotidine 5'-phosphate decarboxylase, which allows a reaction that would otherwise take millions of years to occur in milliseconds. Chemically, enzymes are like any catalyst and are not consumed in chemical reactions, nor do they alter the equilibrium of a reaction. Enzymes differ from most other catalysts by being much more specific. Enzyme activity can be affected by other molecules: inhibitors are molecules that decrease enzyme activity, activators are molecules that increase activity. Many therapeutic drugs and poisons are enzyme inhibitors. An enzyme's activity decreases markedly outside its optimal temperature and pH, many enzymes are denatured when exposed to excessive heat, losing their structure and catalytic properties; some enzymes are used commercially, in the synthesis of antibiotics. Some household products use enzymes to speed up chemical reactions: enzymes in biological washing powders break down protein, starch or fat stains on clothes, enzymes in meat tenderizer break down proteins into smaller molecules, making the meat easier to chew.
By the late 17th and early 18th centuries, the digestion of meat by stomach secretions and the conversion of starch to sugars by plant extracts and saliva were known but the mechanisms by which these occurred had not been identified. French chemist Anselme Payen was the first to discover an enzyme, diastase, in 1833. A few decades when studying the fermentation of sugar to alcohol by yeast, Louis Pasteur concluded that this fermentation was caused by a vital force contained within the yeast cells called "ferments", which were thought to function only within living organisms, he wrote that "alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells."In 1877, German physiologist Wilhelm Kühne first used the term enzyme, which comes from Greek ἔνζυμον, "leavened" or "in yeast", to describe this process. The word enzyme was used to refer to nonliving substances such as pepsin, the word ferment was used to refer to chemical activity produced by living organisms.
Eduard Buchner submitted his first paper on the study of yeast extracts in 1897. In a series of experiments at the University of Berlin, he found that sugar was fermented by yeast extracts when there were no living yeast cells in the mixture, he named the enzyme that brought about the fermentation of sucrose "zymase". In 1907, he received the Nobel Prize in Chemistry for "his discovery of cell-free fermentation". Following Buchner's example, enzymes are named according to the reaction they carry out: the suffix -ase is combined with the name of the substrate or to the type of reaction; the biochemical identity of enzymes was still unknown in the early 1900s. Many scientists observed that enzymatic activity was associated with proteins, but others argued that proteins were carriers for the true enzymes and that proteins per se were incapable of catalysis. In 1926, James B. Sumner crystallized it; the conclusion that pure proteins can be enzymes was definitively demonstrated by John Howard Northrop and Wendell Meredith Stanley, who worked on the digestive enzymes pepsin and chymotrypsin.
These three scientists were awarded the 1946 Nobel Prize in Chemistry. The discovery that enzymes could be crystallized allowed their structures to be solved by x-ray crystallography; this was first done for lysozyme, an enzyme found in tears and egg whites that digests the coating of some bacteria. This high-resolution structure of lysozyme marked the beginning of the field of structural biology and the effort to understand how enzymes work at an atomic level of detail. An enzyme's name is derived from its substrate or the chemical reaction it catalyzes, with the word ending in -ase. Examples are alcohol dehydrogenase and DNA polymerase. Different enzymes that catalyze the same chemical reaction are called isozymes; the International Union of Biochemistry and Molecular Biology have developed a nomenclature for enzymes, the EC numbers. The first number broadly classifies the enzyme based on its mechanism; the top-level classification is: EC 1, Oxidoreductases: catalyze oxidation/reducti
Complement component 1s
Complement component 1s is a protein involved in the complement system. C1s is part of the C1 complex. In humans, it is encoded by the C1S gene. C1s cleaves C4 and C2, which leads to the production of the classical pathway C3-convertase. C1q - another part of the C1 complex C1r - another part of the C1 complex MASP-2 - a protein similar to C1s, part of the lectin pathway Complement+C1s at the US National Library of Medicine Medical Subject Headings Human C1S genome location and C1S gene details page in the UCSC Genome Browser
Chromosome 12 is one of the 23 pairs of chromosomes in humans. People have two copies of this chromosome. Chromosome 12 spans about 133 million base pairs and represents between 4 and 4.5 percent of the total DNA in cells. Chromosome 12 contains the Homeobox C gene cluster; the following are some of the gene count estimates of human chromosome 12. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies. Among various projects, the collaborative consensus coding sequence project takes an conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes; the following is a partial list of genes on human chromosome 12. For complete list, see the link in the infobox on the right; the following diseases are some of those related to genes on chromosome 12: National Institutes of Health. "Chromosome 12". Genetics Home Reference. Retrieved 2017-05-06. "Chromosome 12".
Human Genome Project Information Archive 1990–2003. Retrieved 2017-05-06
Complement component 1q
The complement component 1q is a protein complex involved in the complement system, part of the innate immune system. C1q together with C1s form the C1 complex. Antibodies of the adaptive immune system can bind antigen; when C1q binds antigen-antibody complexes, the C1 complex becomes activated. Activation of the C1 complex initiates the classical complement pathway of the complement system; the antibodies IgM and all IgG subclasses. C1q is a 400 kDa protein formed from 18 peptide chains in 3 subunits of 6; each 6 peptide subunit consists of a Y-shaped pair of triple peptide helices joined at the stem and ending in a globular non-helical head. The 80-amino acid helical component of each triple peptide contain many Gly-X-Y sequences, where X and Y are proline, isoleucine, or hydroxylysine. C1q is composed of 18 polypeptide chains: six A-chains, six B-chains, six C-chains; each chain contains a collagen-like region located near the N terminus and a C-terminal globular region. The A-, B-, C-chains are arranged in the order A-C-B on chromosome 1.
The C1q domain is a conserved protein domain. C1q is a subunit of the C1 enzyme complex. C1q comprises 6 B and 6 C chains; these share the same topology, each possessing a small, globular N-terminal domain, a collagen-like Gly/Pro-rich central region, a conserved C-terminal region, the C1q domain. The C1q protein is produced in collagen-producing cells and shows sequence and structural similarity to collagens VIII and X, it is assumed that the globular ends are the sites for multivalent attachment to the complement fixing sites in immune complexed immunoglobulin. Patients suffering from Lupus erythematosus have deficient expression of C1q. Genetic deficiency of C1q is rare although the majority of those suffer from SLE. C1q may play a central role in the aging of cells. C1q associates with C1r and C1s in order to yield the C1 complex, the first component of the serum complement system. Deficiency of C1q has been associated with lupus glomerulonephritis, it is multivalent for attachment to the complement fixation sites of immunoglobulin.
The sites are on the CH2 domain of IgG and, it is thought, on the CH4 domain of IgM. IgG4 can not bind C1q; the appropriate peptide sequence of the complement fixing site might become exposed following complexing of the immunoglobulin, or the sites might always be available, but might require multiple attachment by C1q with critical geometry in order to achieve the necessary avidity. C1q: structure and receptors. Kishore U1, Reid KB. Immunopharmacology. 2000 Aug. Functional Complement C1q Abnormality Leads to Impaired Immune Complexes and Apoptotic Cell Clearance. Deciphering the fine details of C1 assembly and activation mechanisms: “mission impossible”? - detailed diagrams Complement+C1q at the US National Library of Medicine Medical Subject Headings