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How the Protein Data Bank changed biology: An introduction to the JBC Reviews thematic series, part 2

  • Lila M. Gierasch
    Correspondence
    For correspondence: Helen M. Berman; Lila M. Gierasch
    Affiliations
    Departments of Biochemistry & Molecular Biology and Chemistry, University of Massachusetts, Amherst, Amherst, Massachusetts, USA
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  • Helen M. Berman
    Correspondence
    For correspondence: Helen M. Berman; Lila M. Gierasch
    Affiliations
    Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA

    Department of Biological Sciences and Bridge Institute, University of Southern California, Los Angeles, California, USA
    Search for articles by this author
Open AccessPublished:May 03, 2021DOI:https://doi.org/10.1016/j.jbc.2021.100748
      In part 1 of this remarkable collection, we told you the story of The Protein Data Bank (PDB) (
      • Berman H.M.
      • Gierasch L.M.
      How the Protein Data Bank changed biology: An introduction to the JBC Reviews thematic series, part 1.
      ), which was founded 50 years ago, and we illustrated the breadth of the science contained within it with ten informative review articles. The second half of this collection is a continuation of our celebrations to mark this momentous anniversary. Part 2 provides eight more superb articles describing how the PDB has influenced biology over the course of the last half-century and how biology has fueled the deposition of impactful structures in the PDB. Here are some brief synopses of the articles you will enjoy in part 2!

      Keywords

      Our understanding of cellular signaling is dependent on the knowledge of key protein structures. In their review, Susan S. Taylor (University of California, San Diego) and colleagues use cAMP-dependent protein kinase as a model system to show us the many levels of detail of the structural basis of signaling (
      • Taylor S.S.
      • Wu J.
      • Bruystens J.G.H.
      • Del Rio J.C.
      • Lu T.-W.
      • Kornev A.P.
      • Ten Eyck L.F.
      From structure to the dynamic regulation of a molecular switch: A journey over three decades.
      ). The authors describe the landmark structure of the catalytic subunit of PKA and then explore how the kinase domain is packaged in an inactive state by the cAMP binding regulatory subunits. The review also captures the importance of understanding crystal packing, using multiple structural determination methods, and thinking outside the box.
      Transcriptional regulation is fundamental to cellular homeostasis, coordinating responses to a wide array of physiological signals. In her review, Cynthia Wolberger (The Johns Hopkins University School of Medicine) focuses on how the structures of protein–DNA complexes have provided insights into regulation of transcription (
      • Wolberger C.
      How structural biology transformed studies of transcription regulation.
      ). She describes some of the earliest structures that were determined in the 1980s and explores the structural basis for the remarkable diversity of sequence-specific binding modes. She then discusses the multimeric complexes that are utilized in eukaryotic systems and the ability of cryo-electron microscopy to enable visualization of very large macromolecular complexes with ever-increasing molecular detail, now facilitating the structural understanding of large transcription and elongation machines.
      The field of structural immunology was born 50 years ago with the first determination of antibody structures. In their review, Ian Wilson (The Scripps Research Institute) and his colleague Robyn Stanfield trace how structures were pivotal to our understanding of antibody–antigen interactions and revealed the diversity of the antigen receptors and the antigens in the immune system (
      • Wilson I.A.
      • Stanfield R.L.
      50 Years of structural immunology.
      ). They describe the wealth of structural information we have gathered about viral antigens of enveloped viruses, which are responsible for life-threatening diseases such as influenza, HIV, and COVID-19. The way in which the experimental challenges of sample preparation and structure determination have been overcome highlights the progress that has enabled structural biology to be such an effective method for understanding health and disease.
      Another field of biological science that has emerged hand in hand with the PDB is protein homeostasis—the array of cellular networks dedicated to maintaining the health of the proteome. Helen Saibil (Birkbeck College) provides an exciting and informative review of the evolution of the field of protein homeostasis, from the first structures of chaperonins to the recent elucidation of protein aggregate structures (
      • Saibil H.R.
      The PDB and protein homeostasis: From chaperones to degradation and disaggregase machines.
      ). In parallel, she describes how the determination of these structures has relied increasingly on cryo-electron microscopy. Recent exciting advances that are opening doors to the complex cellular physiology of protein homeostasis include complexes containing multiple chaperones along with their substrates and emerging methods to observe protein homeostasis machines in their cellular context.
      Structural Genomics (SG) as a field unto itself was an outgrowth of the huge amount of data produced by the genome sequencing projects and the resultant challenge of determining the structures of the proteins encoded by every genome. Andrzej Joachimiak (Argonne National Laboratory and University of Chicago) and his colleague Karolina Michalska describe how worldwide structural genomics programs attempted to meet this challenge, developing high-throughput pipelines for all steps en route to structural characterization (
      • Michalska K.
      • Joachimiak A.
      Structural genomics and Protein Data Bank.
      ). These efforts have resulted in a large number of unique structures and vastly improved methods for all of structural biology.
      Traditionally, single methods including X-ray crystallography, NMR spectroscopy, and cryo-electron microscopy were deployed to elucidate macromolecular structures. In recent years, it has been recognized that the data from multiple experimental methods combined with computational modeling empower the determination of integrative models of large macromolecular machines. Andrej Sali (Research Collaboratory for Structural Bioinformatics Protein Data Bank and University of California San Francisco) describes how this type of integrative modeling using results from multiple approaches is done, the challenges it presents, and how a pipeline is being created for archiving these data (
      • Sali A.
      From integrative structural biology to cell biology.
      ). He ends his review by describing the future of integrative “metamodeling,” showing how it can be used to model an entire cell.
      An inadvertent and undesirable outcome from presenting the beautiful structures in the PDB is that they can create an impression that macromolecules are static. George Phillips (Rice University) and his colleague Mitchell Miller dispel this notion, examining the ways in which biomolecular dynamics are studied (
      • Miller M.D.
      • Phillips Jr., G.N.
      Moving beyond static snapshots: Protein dynamics and the Protein Data Bank.
      ). As case studies, they explore the numerous methods that have been used to analyze the binding of gaseous ligands to myoglobin and explore its overall dynamics, as well as the many different analyses of adenylate kinase that have led to a better understanding of its mechanism of catalysis. The use of both free electron lasers and cryo-electron microscopy has made it possible to get much deeper insight into dynamics. A new challenge will be how to best archive protein dynamics data so they will be useful for further research.
      The last review in our collection chronicles how the visualization of macromolecular structure depiction evolved hand in hand with the PDB and advanced the ability of researchers to appreciate and functionally interpret molecular architecture. Jane and David Richardson (Duke University) and David Goodsell (The Scripps Research Institute and Research Collaboratory for Structural Bioinformatics Protein Data Bank) have together changed how we think of macromolecular structure and how we use images to better understand the biological processes we seek to elucidate (
      • Richardson J.S.
      • Richardson D.C.
      • Goodsell D.S.
      Seeing the PDB.
      ). What is even more fun and informative, particularly to those who were not privy to the developments in structure visualization as they emerged, is to see the artistry that underlies the human appreciation for complex three-dimensional molecular structures.
      The compilation of wonderful reviews in this second part of our thematic JBC issue celebrating the 50th anniversary of the PDB, together with the reviews included in part 1, illustrates the spectrum of hugely impressive science enabled by the establishment of the PDB to facilitate open sharing of macromolecular structures. Moreover, it is abundantly clear that the advances in biological science in which the PDB played a role also led to a synergistic evolution of the PDB to serve the scientific community in ever better ways. There is so much to celebrate! And so much wonderful science to embrace! We hope you enjoy the terrific articles in this collection as much as we do.

      Conflict of interest

      The authors declare that they have no conflicts of interest with the contents of this article.

      Acknowledgments

      The authors would like to express their great appreciation for the important contributions of Lucinda Jack and Catherine Goodman to every aspect of the realization of this collection.

      Funding and additional information

      L. M. G. also acknowledges that her work on this collection was supported in part by a grant from the National Institutes of General Medical Sciences ( R35 GM118161 ).

      References

        • Berman H.M.
        • Gierasch L.M.
        How the Protein Data Bank changed biology: An introduction to the JBC Reviews thematic series, part 1.
        J. Biol. Chem. 2021; 296: 100608
        • Taylor S.S.
        • Wu J.
        • Bruystens J.G.H.
        • Del Rio J.C.
        • Lu T.-W.
        • Kornev A.P.
        • Ten Eyck L.F.
        From structure to the dynamic regulation of a molecular switch: A journey over three decades.
        J. Biol. Chem. 2021; 296: 100746
        • Wolberger C.
        How structural biology transformed studies of transcription regulation.
        J. Biol. Chem. 2021; 296: 100741
        • Wilson I.A.
        • Stanfield R.L.
        50 Years of structural immunology.
        J. Biol. Chem. 2021; 296: 100745
        • Saibil H.R.
        The PDB and protein homeostasis: From chaperones to degradation and disaggregase machines.
        J. Biol. Chem. 2021; 296: 100744
        • Michalska K.
        • Joachimiak A.
        Structural genomics and Protein Data Bank.
        J. Biol. Chem. 2021; 296: 100747
        • Sali A.
        From integrative structural biology to cell biology.
        J. Biol. Chem. 2021; 296: 100743
        • Miller M.D.
        • Phillips Jr., G.N.
        Moving beyond static snapshots: Protein dynamics and the Protein Data Bank.
        J. Biol. Chem. 2021; 296: 100749
        • Richardson J.S.
        • Richardson D.C.
        • Goodsell D.S.
        Seeing the PDB.
        J. Biol. Chem. 2021; 296: 100742

      Linked Article

      • How structural biology transformed studies of transcription regulation
        Journal of Biological ChemistryVol. 296
        • Preview
          The past 4 decades have seen remarkable advances in our understanding of the structural basis of gene regulation. Technological advances in protein expression, nucleic acid synthesis, and structural biology made it possible to study the proteins that regulate transcription in the context of ever larger complexes containing proteins bound to DNA. This review, written on the occasion of the 50th anniversary of the founding of the Protein Data Bank focuses on the insights gained from structural studies of protein–DNA complexes and the role the PDB has played in driving this research.
        • Full-Text
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        Open Access
      • Moving beyond static snapshots: Protein dynamics and the Protein Data Bank
        Journal of Biological ChemistryVol. 296
        • Preview
          Proteins are the molecular machines of living systems. Their dynamics are an intrinsic part of their evolutionary selection in carrying out their biological functions. Although the dynamics are more difficult to observe than a static, average structure, we are beginning to observe these dynamics and form sound mechanistic connections between structure, dynamics, and function. This progress is highlighted in case studies from myoglobin and adenylate kinase to the ribosome and molecular motors where these molecules are being probed with a multitude of techniques across many timescales.
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        Open Access
      • 50 Years of structural immunology
        Journal of Biological ChemistryVol. 296
        • Preview
          Fifty years ago, the first landmark structures of antibodies heralded the dawn of structural immunology. Momentum then started to build toward understanding how antibodies could recognize the vast universe of potential antigens and how antibody-combining sites could be tailored to engage antigens with high specificity and affinity through recombination of germline genes (V, D, J) and somatic mutation. Equivalent groundbreaking structures in the cellular immune system appeared some 15 to 20 years later and illustrated how processed protein antigens in the form of peptides are presented by MHC molecules to T cell receptors.
        • Full-Text
        • PDF
        Open Access
      • The PDB and protein homeostasis: From chaperones to degradation and disaggregase machines
        Journal of Biological ChemistryVol. 296
        • Preview
          This review contains a personal account of the role played by the PDB in the development of the field of molecular chaperones and protein homeostasis, from the viewpoint of someone who experienced the concurrent advances in the structural biology, electron microscopy, and chaperone fields. The emphasis is on some key structures, including those of Hsp70, GroEL, Hsp90, and small heat shock proteins, that were determined as the molecular chaperone concept and systems for protein quality control were emerging.
        • Full-Text
        • PDF
        Open Access
      • From structure to the dynamic regulation of a molecular switch: A journey over 3 decades
        Journal of Biological ChemistryVol. 296
        • Preview
          It is difficult to imagine where the signaling community would be today without the Protein Data Bank. This visionary resource, established in the 1970s, has been an essential partner for sharing information between academics and industry for over 3 decades. We describe here the history of our journey with the protein kinases using cAMP-dependent protein kinase as a prototype. We summarize what we have learned since the first structure, published in 1991, why our journey is still ongoing, and why it has been essential to share our structural information.
        • Full-Text
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        Open Access
      • Structural genomics and the Protein Data Bank
        Journal of Biological ChemistryVol. 296
        • Preview
          The field of Structural Genomics arose over the last 3 decades to address a large and rapidly growing divergence between microbial genomic, functional, and structural data. Several international programs took advantage of the vast genomic sequence information and evaluated the feasibility of structure determination for expanded and newly discovered protein families. As a consequence, structural genomics has developed structure-determination pipelines and applied them to a wide range of novel, uncharacterized proteins, often from “microbial dark matter,” and later to proteins from human pathogens.
        • Full-Text
        • PDF
        Open Access
      • Seeing the PDB
        Journal of Biological ChemistryVol. 296
        • Preview
          Ever since the first structures of proteins were determined in the 1960s, structural biologists have required methods to visualize biomolecular structures, both as an essential tool for their research and also to promote 3D comprehension of structural results by a wide audience of researchers, students, and the general public. In this review to celebrate the 50th anniversary of the Protein Data Bank, we present our own experiences in developing and applying methods of visualization and analysis to the ever-expanding archive of protein and nucleic acid structures in the worldwide Protein Data Bank.
        • Full-Text
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        Open Access
      • From integrative structural biology to cell biology
        Journal of Biological ChemistryVol. 296
        • Preview
          Integrative modeling is an increasingly important tool in structural biology, providing structures by combining data from varied experimental methods and prior information. As a result, molecular architectures of large, heterogeneous, and dynamic systems, such as the ∼52-MDa Nuclear Pore Complex, can be mapped with useful accuracy, precision, and completeness. Key challenges in improving integrative modeling include expanding model representations, increasing the variety of input data and prior information, quantifying a match between input information and a model in a Bayesian fashion, inventing more efficient structural sampling, as well as developing better model validation, analysis, and visualization.
        • Full-Text
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        Open Access