The Protein Data Bank (PDB; http://www.rcsb.org/pdb/ ) is the single worldwide archive of structural data of biological macromolecules. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.

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The Protein Data Bank

We describe a graphical system for automatically generating multiple 2D diagrams of ligand–protein interactions from 3D coordinates. The diagrams portray the hydrogen-bond interaction patterns and hydrophobic contacts between the ligand(s) and the main-chain or side-chain elements of the protein. The system is able to plot, in the same orientation, related sets of ligand–protein interactions. This facilitates popular research tasks, such as analyzing a series of small molecules binding to the same protein target, a single ligand binding to homologous proteins, or the completely general case where both protein and ligand change.

LigPlot+: multiple ligand-protein interaction diagrams for drug discovery.

We present ShapeNet: a richly-annotated, large-scale repository of shapes represented by 3D CAD models of objects. ShapeNet contains 3D models from a multitude of semantic categories and organizes them under the WordNet taxonomy. It is a collection of datasets providing many semantic annotations for each 3D model such as consistent rigid alignments, parts and bilateral symmetry planes, physical sizes, keywords, as well as other planned annotations. Annotations are made available through a public web-based interface to enable data visualization of object attributes, promote data-driven geometric analysis, and provide a large-scale quantitative benchmark for research in computer graphics and vision. At the time of this technical report, ShapeNet has indexed more than 3,000,000 models, 220,000 models out of which are classified into 3,135 categories (WordNet synsets). In this report we describe the ShapeNet effort as a whole, provide details for all currently available datasets, and summarize future plans.

ShapeNet: An Information-Rich 3D Model Repository

Oestrogens are involved in the growth, development and homeostasis of a number of tissues. The physiological effects of these steroids are mediated by a ligand-inducible nuclear transcription factor, the oestrogen receptor (ER). Hormone binding to the ligand-binding domain (LBD) of the ER initiates a series of molecular events culminating in the activation or repression of target genes. Transcriptional regulation arises from the direct interaction of the ER with components of the cellular transcription machinery. Here we report the crystal structures of the LBD of ER in complex with the endogenous oestrogen, 17beta-oestradiol, and the selective antagonist raloxifene, at resolutions of 3.1 and 2.6 A, respectively. The structures provide a molecular basis for the distinctive pharmacophore of the ER and its catholic binding properties. Agonist and antagonist bind at the same site within the core of the LBD but demonstrate different binding modes. In addition, each class of ligand induces a distinct conformation in the transactivation domain of the LBD, providing structural evidence of the mechanism of antagonism.

Molecular basis of agonism and antagonism in the oestrogen receptor.

The Structural Basis of Estrogen Receptor/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen

The LIGPLOT program automatically generates schematic 2-D representations of protein-ligand complexes from standard Protein Data Bank file input. The output is a colour, or black-and-white, PostScript file giving a simple and informative representation of the intermolecular interactions and their strengths, including hydrogen bonds, hydrophobic interactions and atom accessibilities. The program is completely general for any ligand and can also be used to show other types of interaction in proteins and nucleic acids. It was designed to facilitate the rapid inspection of many enzyme complexes, but has found many other applications.

LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions

PDBsum: a web-based database of summaries and analyses of all PDB structures

It is well established that sequence templates such as those in the PROSITE and PRINTS databases are powerful tools for predicting the biological function and tertiary structure for newly derived protein sequences. The number of X-ray and NMR protein structures is increasing rapidly and it is apparent that a 3D equivalent of the sequence templates is needed. Here, we describe an algorithm called TESS that automatically derives 3D templates from structures deposited in the Brookhaven Protein Data Bank. While a new sequence can be searched for sequence patterns, a new structure can be scanned against these 3D templates to identify functional sites. As examples, 3D templates are derived for enzymes with an O-His-O "catalytic triad" and for the ribonucleases and lysozymes. When these 3D templates are applied to a large data set of nonidentical proteins, several interesting hits are located. This suggests that the development of a 3D template database may help to identify the function of new protein structures, if unknown, as well as to design proteins with specific functions.

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Tess: A geometric hashing algorithm for deriving 3D coordinate templates for searching structural databases. Application to enzyme active sites

It is well established that sequence templates (e.g., PROSITE) and databases are powerful tools for identifying biological function and tertiary structure for an unknown protein sequence. Here we describe a method for automatically deriving 3D templates from the protein structures deposited in the Brookhaven Protein Data Bank. As an example, we describe a template derived for the Ser-His-Asp catalytic triad found in the serine proteases and triacylglycerol lipases. We find that the resultant template provides a highly selective tool for automatically differentiating between catalytic and noncatalytic Ser-His-Asp associations. When applied to nonproteolytic proteins, the template picks out two "non-esterase" catalytic triads that may be of biological relevance. This suggests that the development of databases of 3D templates, such as those that currently exist for protein sequence templates, will help identify the functions of new protein structures as they are determined and pinpoint their functionally important regions.

Derivation of 3D coordinate templates for searching structural databases: application to Ser-His-Asp catalytic triads in the serine proteinases and lipases.

Introduction The number of protein complexes whose threedimensional structures have been determined is rising rapidly. The Protein Data Bank (PDB [ 13) now includes many examples of protein-protein, protein-hapten, protein-DNA and proteincarbohydrate complexes. Continuing improvements in X-ray crystallography have allowed some of these structures to be determined to high resolution, giving a more accurate picture of the details of specific non-covalent interactions. Furthermore, the technique of molecular replacement has made it easier to determine the structures of closely related proteins, such as members of related families or cases where the same protein is complexed with different ligands. For example, there are almost 200 different serine proteinase structures in the PDB complexed with a wide variety of ligands. Thus, we are now at a stage when it is valuable to bring together information from many structures, with the aim of deriving general principles of molecular recognition, to help in the knowledge-based prediction and modelling of unknown complexes. In this paper we present the results of some of our recent work on protein-small ligand interactions. (Parallel work on protein-protein interactions will not be presented here because of lack of space.) The results cover three related aspects of molecular recognition. Firstly, since we wished to consider the structures of many different protein-ligand complexes, it was necessary to develop a software tool that would quickly and easily allow us to calculate, display and inspect the interactions between a protein and its ligand. The program LIGPLOT addresses this problem. Secondly, we wished to compare and contrast enzyme active sites, and consider the evolutionary constraints on a system, which is required to perform catalysis. We began this task by considering the Ser-His-Asp catalytic triad found in the serine proteinases and several other enyzme families. We have developed an approach that involves deriving three-dimensional co-ordinate

Andrew C. Wallace

Papers

LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions

PDBsum: a web-based database of summaries and analyses of all PDB structures

Tess: A geometric hashing algorithm for deriving 3D coordinate templates for searching structural databases. Application to enzyme active sites

Derivation of 3D coordinate templates for searching structural databases: application to Ser-His-Asp catalytic triads in the serine proteinases and lipases.

Molecular recognition by proteins: protein-ligand interactions from a structural perspective.