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  • Review Article
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Understanding the molecular machinery of genetics through 3D structures

Nature Reviews Genetics volume 9, pages 141–151 (2008)Cite this article

Key Points

  • Knowledge of the 3D structures of biological molecules can reveal the fine details of how the molecules perform their biological functions.

  • The principal experimental techniques for determining 3D structure are X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. In addition, recent advances in electron microscopy, cryo-electron microscopy and electron cryo-tomography have enabled low-resolution structures of large structures, such as those of viruses and large macromolecular assemblies, to be determined.

  • Homology modelling allows the 3D structures of proteins to be computed from their sequence, based on the structure of a close relative. However, great care must be taken when drawing conclusions on the basis of these models as they are often not sufficiently accurate for predicting detailed or subtle structural changes.

  • 3D structure has contributed greatly to our understanding of protein evolution as structure tends to be more strongly conserved over evolutionary time than sequence. Structural similarity can reveal distant evolutionary relationships between proteins that cannot be detected from comparison of their sequences alone.

  • Most single amino-acid changes to a protein's sequence have little effect on structure. Some, however, such as the point mutations that are known to be associated with inherited monogenic diseases, have catastrophic consequences.

  • Most disease-associated missense mutations affect either the stability of the associated protein or its ability to fold. Others interfere with its biological function by disrupting its ability to interact with other molecules.

  • Sequence insertions and deletions can be accommodated over evolutionary time within a protein's structure without significantly altering its overall fold.

  • Alternative splicing of genes can result in different protein products with different functions. In some cases, the change of function can be explained by the consequent change in structure (for example, by the loss or gain of a functional structural domain, or by the subtle modification of the substrate binding site). In most cases, however, the structural differences between splice isoforms are not known (and are difficult to model reliably), so the consequences are difficult to predict.

  • The X-ray structure of the nucleosome core particle has revealed the large-scale packaging of DNA in chromatin. This, together with the knowledge of the histone proteins and the modifications they can undergo, is a first step in the understanding of the encoding, inheritance and recognition of epigenetic information.

  • The phenotypic differences observed both within and between species result both from differences in the genome sequences and in the regulatory networks through which the genes are expressed. Structural studies have helped to reveal how many of the simpler mechanisms that regulate gene expression operate.

  • Although there are currently 47,000 3D structures of biomolecules known, this is a tiny fraction of the 105 million known protein sequences. Several structural genomics projects worldwide are applying high-throughput technologies for structure determination in an attempt to address this shortfall.

Abstract

Detailed knowledge of the three-dimensional structures of biological molecules has had an enormous impact on all areas of biological science, including genetics, as structure can reveal the fine details of how molecules perform their biological functions. Here we consider how changes in protein sequence affect the corresponding 3D structure, and describe how structural information about proteins, DNA and chromatin has shed light on gene regulatory mechanisms and the storage and transmission of epigenetic information. Finally, we describe how structure determination is benefiting from the high-throughput technologies of the worldwide structural genomics projects.

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Figure 1: Timeline of solved structures of some key biomolecules.
Figure 2: The effect of mutations on structure.
Figure 3: The pitfalls of relying on homology-built models.
Figure 4: Suggested structure for the 30 nm chromatin fibre.
Figure 5: The three most common structural motifs used by proteins to recognize and bind to DNA.

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Authors and Affiliations

  1. European Bioinformatics Institute, European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, CB10 1SD, Cambridge, UK

    Roman A. Laskowski & Janet M. Thornton

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  1. Roman A. Laskowski
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Correspondence to Roman A. Laskowski.

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DATABASES

PDBsum

1aay

1aoi

1fok

1f66

1gm1

1hio

1kna

1kne

1ozi

1pfb

1rh8

1rj7

1rj8

1vj6

1ysa

1zbb

2ffl

FURTHER INFORMATION

Thornton Group homepage

Human Gene Mutation Database

PyMol

SWISS-MODEL

SwissProt

TrEMBL

Glossary

B-DNA

Standard form of double-stranded DNA.

Fold

The arrangement and connectivity of the regions of regular secondary structure, adopted by a given structural domain.

Fold group

A grouping of similar folds, often merely referred to as a fold.

Structural domain

A compact part of the protein's 3D structure that is capable of folding independently of any of a protein's other domains. Structural domains often, but not always, correspond to sequence domains.

PDB

(Protein Data Bank). The archive of experimentally determined structures of proteins, RNA and fragments of DNA (see Box 1).

Secondary structure

Segments of the protein chain that show a regular local structure: coiling into an α-helical segment, or extending to form a β-strand that links up side-by-side with others to form a β-sheet.

Rational engineering

Use of site-directed mutagenesis to make specific alterations to an enzyme's structure, specificity or catalytic activity.

Directed evolution

Cycles of error-prone PCR introduce random point mutations into a small pool of homologous genes with the selection of gene products that have required properties at each cycle.

Pfam

A manually curated database of protein families.

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Laskowski, R., Thornton, J. Understanding the molecular machinery of genetics through 3D structures. Nat Rev Genet 9, 141–151 (2008). https://doi.org/10.1038/nrg2273

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