RCSB Protein Data Bank tools for 3D structure-guided cancer research: human papillomavirus (HPV) case study - PubMed (original) (raw)

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RCSB Protein Data Bank tools for 3D structure-guided cancer research: human papillomavirus (HPV) case study

David S Goodsell et al. Oncogene. 2020 Oct.

Abstract

Atomic-level three-dimensional (3D) structure data for biological macromolecules often prove critical to dissecting and understanding the precise mechanisms of action of cancer-related proteins and their diverse roles in oncogenic transformation, proliferation, and metastasis. They are also used extensively to identify potentially druggable targets and facilitate discovery and development of both small-molecule and biologic drugs that are today benefiting individuals diagnosed with cancer around the world. 3D structures of biomolecules (including proteins, DNA, RNA, and their complexes with one another, drugs, and other small molecules) are freely distributed by the open-access Protein Data Bank (PDB). This global data repository is used by millions of scientists and educators working in the areas of drug discovery, vaccine design, and biomedical and biotechnology research. The US Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB) provides an integrated portal to the PDB archive that streamlines access for millions of worldwide PDB data consumers worldwide. Herein, we review online resources made available free of charge by the RCSB PDB to basic and applied researchers, healthcare providers, educators and their students, patients and their families, and the curious public. We exemplify the value of understanding cancer-related proteins in 3D with a case study focused on human papillomavirus.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1

Fig. 1. Multiple options streamline searches of the PDB archive.

Here, HPV16 holdings were found by (a) searching for “papillomavirus” in the main search box, b selecting HPV16 in the refinement options, and c choosing a gallery display. Advanced searches may be built-in (d) for more specific queries. The search returns several L1 capsid structures, some coated with antibody Fab fragments, and structures of E2 and E6, some interacting with host cell proteins.

Fig. 2

Fig. 2. Structure Summary pages provide an overview for each entry in the PDB archive.

Structure Summary for a cryo-electron microscopy study of HPV16 capsid (PDB ID 3j6r [19]) provides an overview of the entry and many options to access detailed information and analysis tools.

Fig. 3

Fig. 3. The Protein Feature view summarizes all PDB entries for a particular protein.

Protein Feature view for a complex of HPV16 E6 with guanylate kinase MAGI-1 (PDB ID 2kpl [24]) helps users understand that only a small peptide from E6 is included in the PDB ID. A similar View is available for MAGI-1, showing that only one domain from that protein is included in the entry.

Fig. 4

Fig. 4. Sequence and structure alignments allow analysis of conservation and flexibility.

Comparison of L1 proteins from pentamers of HPV11 (cyan, PDB ID 2r5k [31]) and HPV18 (orange, PDB ID 2r5i [31]), using the Java Web Start “Structure Alignment” tool. Arrows indicate sites with changes in the length of loops, seen as gaps in the sequence alignment at the top.

Fig. 5

Fig. 5. Visualization of virus-host interactions with Mol*.

Left: HPV E6 brings together E6AP and p53 tumor suppressor (PDB ID 4xr8 [34]). Only portions of E6AP and p53 are included in the structure determination, and E6AP was studied as a chimera with maltose binding protein. Right: interaction of p107 with E6 and with a suboptimal host partner (PDB IDs 4yos, 4yoz [35]).

Fig. 6

Fig. 6. Visualization of epitopes with JSmol.

Epitopes (red) of antibodies U4 (left) and V5 (right) on HPV16 capsids, visualized with online JSmol scripting tools (PDB IDs 6bsp, 6bt3 [37]).

Fig. 7

Fig. 7. Outreach materials introduce structural topics to a wide audience.

Outreach materials include a feature and a foldable paper model of HPV (red) bound to antibody Fab fragments (blue) (PDB ID 6bt3 [37]*).

References

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