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X-Ray Crystallography
/ EKS-ray kris-tuh-LAH-gruh-fee / · From German X-Strahl, unknown ray, Greek krystallos, ice or crystal, and Greek graphein, to write.
X-Ray Crystallography is a biophysical technique that determines the three-dimensional atomic structure of a molecule by analyzing the diffraction pattern produced when X-rays pass through a crystallized sample.
The technique requires growing high-quality crystals, often the rate-limiting step, followed by exposing them to an intense X-ray beam and recording the resulting diffraction pattern. Fourier transformation of that pattern generates an electron density map into which an atomic model is built and refined, sometimes to resolutions better than 1 angstrom. Historic achievements include Rosalind Franklin’s 1952 diffraction image of DNA, designated Photo 51, which provided key evidence for the double-helical structure, and the 2009 Nobel Prize awarded for ribosome structures solved by Ada Yonath, Venkatraman Ramakrishnan, and Thomas Steitz.
More than 150,000 protein structures deposited in the Protein Data Bank were determined primarily by this method, and synchrotron radiation sources have accelerated data collection by providing X-ray beams orders of magnitude more intense than laboratory sources.
Serial femtosecond crystallography, developed at free-electron laser facilities such as the Linac Coherent Light Source in California, fires X-ray pulses lasting just 40 femtoseconds at single nanocrystals too small to use in conventional crystallography, capturing diffraction data before radiation damage can destroy the sample.
X-ray crystallography produces direct photographs of molecules. The technique records diffraction patterns, not images; reconstructing a molecular structure requires extensive mathematical analysis, including Fourier transformation, before any atomic positions become visible.
In 2020, researchers at the Diamond Light Source synchrotron in the United Kingdom solved the structure of the SARS-CoV-2 main protease bound to inhibitor compounds within weeks of receiving the first samples. The active site was resolved to 1.39 angstroms, precise enough to guide the design of antiviral drugs targeting that enzyme.
Xenobiotics Response Element
/ ZEE-noh-by-OT-ik reh-SPON-ses EL-eh-ment / · Greek xenos (foreign) + bios (life)
Xenobiotics Response Element is a short DNA regulatory sequence that, when bound by the ligand-activated aryl hydrocarbon receptor complex, switches on genes encoding detoxification enzymes.
Xenobiotics such as polycyclic aromatic hydrocarbons and dioxins bind the cytosolic aryl hydrocarbon receptor, causing it to translocate to the nucleus and dimerize with the ARNT protein. That heterodimer then binds XRE sequences upstream of target genes including CYP1A1, CYP1B1, and glutathione S-transferases, inducing enzymes that metabolize and clear foreign compounds. The XRE core sequence spans only 9 base pairs with the consensus motif GCGTG, yet a single XRE can increase nearby gene transcription by up to 50-fold.
Dysregulation of the AhR-XRE pathway by persistent environmental pollutants such as TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is linked to carcinogenesis and endocrine disruption in both wildlife and humans.
Some detoxification genes carry multiple XREs in their regulatory regions; the human CYP1A1 gene contains four XREs, and dioxin exposure can induce its expression more than 200-fold, making it one of the most strongly inducible genes in the human genome.
Detoxification genes turn on randomly after chemical exposure. Specific regulatory sequences upstream of each detoxification gene determine which chemicals trigger a transcriptional response and by how much.
In rainbow trout (Oncorhynchus mykiss) exposed to benzo[a]pyrene, the aryl hydrocarbon receptor binds XREs upstream of the CYP1A1 gene in liver cells. CYP1A1 transcript levels rise more than 100-fold within 24 hours of exposure, a response used in environmental monitoring to detect polycyclic aromatic hydrocarbon contamination in waterways.