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Instruments / Technical Area	Publication Details	Published
Krios III-Titan Krios III at Diamond	Mechanism of ribosome stalling during translation of a poly(A) tail Viswanathan Chandrasekaran , Szymon Juszkiewicz , Junhong Choi , Joseph D. Puglisi , Alan Brown , Sichen Shao , V. Ramakrishnan , Ramanujan S. Hegde Nature Structural & Molecular Biology 26, 1132 - 1140 DOI: 10.1038/s41594-019-0331-x Diamond Proposal Number(s): [17434] Show Abstract ▼ Abstract: Faulty or damaged messenger RNAs are detected by the cell when translating ribosomes stall during elongation and trigger pathways of mRNA decay, nascent protein degradation and ribosome recycling. The most common mRNA defect in eukaryotes is probably inappropriate polyadenylation at near-cognate sites within the coding region. How ribosomes stall selectively when they encounter poly(A) is unclear. Here, we use biochemical and structural approaches in mammalian systems to show that poly-lysine, encoded by poly(A), favors a peptidyl-transfer RNA conformation suboptimal for peptide bond formation. This conformation partially slows elongation, permitting poly(A) mRNA in the ribosome’s decoding center to adopt a ribosomal RNA-stabilized single-stranded helix. The reconfigured decoding center clashes with incoming aminoacyl-tRNA, thereby precluding elongation. Thus, coincidence detection of poly-lysine in the exit tunnel and poly(A) in the decoding center allows ribosomes to detect aberrant mRNAs selectively, stall elongation and trigger downstream quality control pathways essential for cellular homeostasis.	Nov 2019
I04-Macromolecular Crystallography	Bactobolin A Binds to a Site on the 70S Ribosome Distinct from Previously Seen Antibiotics Alexey Amunts , Karol Fiedorczuk , Thao T. Truong , Josephine Chandler , E. Peter Greenberg , V. Ramakrishnan Journal Of Molecular Biology 427 (4), 753 - 755 DOI: 10.1016/j.jmb.2014.12.018 PMID: 25562208 Open Access Show Abstract ▼ Abstract: The ribosome is the target of a large number of antibiotics. Here, we report a 3.4-Å-resolution crystal structure of bactobolin A bound to 70S ribosome–tRNA complex. The antibiotic binds at a previously unseen site in the 50S subunit and displaces tRNA bound at the P-site. It thus likely has a similar mechanism of action as blasticidin S despite binding to a different site. The structure also rationalizes previously identified resistance mutations.	Feb 2015
	The Diamond Light Source and the challenges ahead for structural biology: some informal remarks V. Ramakrishnan Philosophical Transactions Of The Royal Society A: Mathematical, Physical And Engineering Sciences 373 (2036), 20130156 - 20130156 DOI: 10.1098/rsta.2013.0156 PMID: 25624524 Show Abstract ▼ Abstract: The remarkable advances in structural biology in the past three decades have led to the determination of increasingly complex structures that lie at the heart of many important biological processes. Many of these advances have been made possible by the use of X-ray crystallography using synchrotron radiation. In this short article, some of the challenges and prospects that lie ahead will be summarized. The first crystal structures of macromolecules were determined about half a century ago by Perutz, Kendrew and their colleagues. Even after the realization that isomorphous replacement could yield phase information for protein crystals [1], it still took another decade to obtain the first atomic structures. Although better computing and the advent of area detectors improved the situation considerably over the next two decades, macromolecular crystallography remained a multiyear effort. However, beginning around 1980, the situation began to change dramatically. The idea that synchrotron radiation, normally a ‘waste product’ for high-energy physicists, could be used to produce very high-intensity beams for diffraction studies had led to the construction of several beamlines designed for macromolecular crystallography, beginning with the one at DESY in Hamburg [2]. High-intensity beams led to significantly higher radiation damage. Such damage was greatly minimized by the advent of cryo-crystallography, involving data collection below 100 K [3]. The use of cryo-crystallography with accurate image plate detectors that could scan in situ [4,5] meant that often a complete dataset could be collected from a single crystal in an automated manner and without interruption.	Jan 2015
I04-Macromolecular Crystallography	Unusual base pairing during the decoding of a stop codon by the ribosome Israel S. Fernandez , Chyan Leong Ng , Ann C. Kelley , Guowei Wu , Yi-tao Yu , V. Ramakrishnan Nature 500 (7460), 107 - 110 DOI: 10.1038/nature12302 PMID: 23812587 Open Access Show Abstract ▼ Abstract: During normal translation, the binding of a release factor to one of the three stop codons (UGA, UAA or UAG) results in the termination of protein synthesis. However, modification of the initial uridine to a pseudouridine (Ψ) allows efficient recognition and read-through of these stop codons by a transfer RNA (tRNA), although it requires the formation of two normally forbidden purine–purine base pairs1. Here we determined the crystal structure at 3.1 Å resolution of the 30S ribosomal subunit in complex with the anticodon stem loop of tRNASer bound to the ΨAG stop codon in the A site. The ΨA base pair at the first position is accompanied by the formation of purine–purine base pairs at the second and third positions of the codon, which show an unusual Watson–Crick/Hoogsteen geometry. The structure shows a previously unsuspected ability of the ribosomal decoding centre to accommodate non-canonical base pairs.	Jun 2013
I04-Macromolecular Crystallography	Elongation Factor G Bound to the Ribosome in an Intermediate State of Translocation David S. Tourigny , Israel S. Fernandez , Ann C. Kelley , V. Ramakrishnan Science 340 (6140), 1235490 - 1235490 DOI: 10.1126/science.1235490 PMID: 23812720 Show Abstract ▼ Abstract: A key step of translation by the ribosome is translocation, which involves the movement of messenger RNA (mRNA) and transfer RNA (tRNA) with respect to the ribosome. This allows a new round of protein chain elongation by placing the next mRNA codon in the A site of the 30S subunit. Translocation proceeds through an intermediate state in which the acceptor ends of the tRNAs have moved with respect to the 50S subunit but not the 30S subunit, to form hybrid states. The guanosine triphosphatase (GTPase) elongation factor G (EF-G) catalyzes the subsequent movement of mRNA and tRNA with respect to the 30S subunit. Here, we present a crystal structure at 3 angstrom resolution of the Thermus thermophilus ribosome with a tRNA in the hybrid P/E state bound to EF-G with a GTP analog. The structure provides insights into structural changes that facilitate translocation and suggests a common GTPase mechanism for EF-G and elongation factor Tu.	Jun 2013
I04-Macromolecular Crystallography	Crystal Structure of a Bioactive Pactamycin Analog Bound to the 30S Ribosomal Subunit David S. Tourigny , Israel S. Fernandez , Ann C. Kelley , Ramkrishna Reddy Vakiti , Amit Kumar Chattopadhyay , Stéphane Dorich , Stephen Hanessian , V. Ramakrishnan Journal Of Molecular Biology DOI: 10.1016/j.jmb.2013.05.004 PMID: 23702293 Open Access Show Abstract ▼ Abstract: Biosynthetically and chemically derived analogs of the antibiotic pactamycin and de-6-methylsalicylyl (MSA)-pactamycin have attracted recent interest as potential antiprotozoal and antitumor drugs. Here, we report a 3.1-Å crystal structure of de-6-MSA-pactamycin bound to its target site on the Thermus thermophilus 30S ribosomal subunit. Although de-6-MSA-pactamycin lacks the MSA moiety, it shares the same binding site as pactamycin and induces a displacement of nucleic acid template bound at the E-site of the 30S. The structure highlights unique interactions between this pactamycin analog and the ribosome, which paves the way for therapeutic development of related compounds.	May 2013

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