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Conformational Flux
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- June 4, 2012
- 08:38 PM
- 214 views
Proving conformational selection is hard
by Michael Clarkson in Conformational Flux
Allosteric regulation of proteins is often examined using two different models. The widely-known “induced-fit” (IF) model proposes that effectors form a loose complex with inactive proteins and cause them to shift into a new, active conformation. In the competing “conformational selection” model, effectors bind to and stabilize proteins that are already in an active conformation. [...]... Read more »
Hatzakis, N., Wei, L., Jorgensen, S., Kunding, A., Bolinger, P., Ehrlich, N., Makarov, I., Skjot, M., Svendsen, A., Hedegård, P.... (2012) Single Enzyme Studies Reveal the Existence of Discrete Functional States for Monomeric Enzymes and How They Are “Selected” upon Allosteric Regulation. Journal of the American Chemical Society, 2147483647. DOI: 10.1021/ja3011429
- February 29, 2012
- 09:46 PM
- 306 views
A fluorescent protein viscometer
by Michael Clarkson in Conformational Flux
Fluorescent sensors, be they proteins or small molecules, are extremely useful because they can be used to detect metabolic states and protein interactions in living cells. Fluorescent proteins are particularly useful because they can be produced inside the cell and, using tags, targeted to specific proteins, locations and organelles quite easily. Because of this, a [...]... Read more »
Kao, Y., Zhu, X., & Min, W. (2012) Protein-flexibility mediated coupling between photoswitching kinetics and surrounding viscosity of a photochromic fluorescent protein. Proceedings of the National Academy of Sciences, 109(9), 3220-3225. DOI: 10.1073/pnas.1115311109
- February 1, 2012
- 10:01 PM
- 301 views
Crystallography in a cell
by Michael Clarkson in Conformational Flux
In previous posts on this blog I’ve discussed efforts to perform NMR inside of living cells. These experiments, performed in bacteria, are primarily intended to establish whether dilute-solution experiments veridically reproduce biomolecular structures as they appear in live organisms. Now it seems that crystallography is starting to get in on the act. This week in [...]... Read more »
Koopmann, R., Cupelli, K., Redecke, L., Nass, K., DePonte, D., White, T., Stellato, F., Rehders, D., Liang, M., Andreasson, J.... (2012) In vivo protein crystallization opens new routes in structural biology. Nature Methods. DOI: 10.1038/nmeth.1859
- January 25, 2012
- 09:47 PM
- 293 views
Crowdsourcing enzyme design with Foldit
by Michael Clarkson in Conformational Flux
Imagine that you could get an injection of a protein that would chop up arterial plaques. Imagine that you could drop a plastic bottle into a pool of bacteria that would transform it back into high-grade oil. Imagine that you could take any organic material at all and, with a minimum of planning, transform it [...]... Read more »
Eiben, C., Siegel, J., Bale, J., Cooper, S., Khatib, F., Shen, B., Players, F., Stoddard, B., Popovic, Z., & Baker, D. (2012) Increased Diels-Alderase activity through backbone remodeling guided by Foldit players. Nature Biotechnology. DOI: 10.1038/nbt.2109
- January 17, 2012
- 08:26 PM
- 313 views
Better structural biology through destruction
by Michael Clarkson in Conformational Flux
While crystallography and NMR are useful for defining the structural characteristics of proteins, cryo-electron microscopy (cryo-EM) may be the most useful technique for investigating the structure of large biomolecular assemblies. Rapid advances in the technique have brought it to the point where it can deliver atomic-resolution models, without the need for crystallization or any relevant [...]... Read more »
Wu, W., Thomas, J., Cheng, N., Black, L., & Steven, A. (2012) Bubblegrams Reveal the Inner Body of Bacteriophage . Science, 335(6065), 182-182. DOI: 10.1126/science.1214120
- January 4, 2012
- 09:10 PM
- 416 views
A Multidrug Resistance Protein Caught in the Act
by Michael Clarkson in Conformational Flux
One of the most serious challenges facing medical science today is the development of drug resistance by bacteria and viruses. Almost as quickly as we can develop drugs that attack the machinery of infectious disease, evolution, aided in some cases by careless use, defeats our efforts. In some cases this is because the specific target [...]... Read more »
Morrison, E., DeKoster, G., Dutta, S., Vafabakhsh, R., Clarkson, M.W., Bahl, A., Kern, D., Ha, T., & Henzler-Wildman, K. (2011) Antiparallel EmrE exports drugs by exchanging between asymmetric structures. Nature, 481(7379), 45-50. DOI: 10.1038/nature10703
- September 20, 2011
- 08:39 PM
- 664 views
Gamers predict protein structures
by Michael Clarkson in Conformational Flux
One of the goals of computational biology is to predict the complete high-order structure of a protein from its amino acid sequence. Often reasonably good structures can be produced by modeling a new protein according to an already-known structure of a homologous protein, one with a similar sequence and presumably a similar structure. However, these [...]... Read more »
Khatib, F., DiMaio, F., Cooper, S., Kazmierczyk, M., Gilski, M., Krzywda, S., Zabranska, H., Pichova, I., Thompson, J., Popović, Z.... (2011) Crystal structure of a monomeric retroviral protease solved by protein folding game players. Nature Structural . DOI: 10.1038/nsmb.2119
- September 19, 2011
- 08:21 PM
- 828 views
Can videogames help treat amblyopia?
by Michael Clarkson in Conformational Flux
Given that videogames are often demonized by research (and “research”) blaming them for everything from rudeness to the epidemic of youth violence, gamers often take a great deal of cheer from research attaching positive outcomes to videogame play. One such article that recently attracted some attention was work suggesting that playing videogames could correct amblyopia [...]... Read more »
Li, R., Ngo, C., Nguyen, J., & Levi, D. (2011) Video-Game Play Induces Plasticity in the Visual System of Adults with Amblyopia. PLoS Biology, 9(8). DOI: 10.1371/journal.pbio.1001135
- September 6, 2011
- 07:00 PM
- 630 views
Solving a transient structure with NMR
by Michael Clarkson in Conformational Flux
Over the last two decades, multiple kinds of NMR experiments have repeatedly shown that protein structures are quite variable, frequently shifting to minor conformations. The most striking evidence in this line has come from hydrogen-exchange experiments, which have demonstrated that virtually all proteins undergo excursions to partially-folded states at equilibrium. As R2 relaxation-dispersion experiments have [...]... Read more »
Bouvignies, G., Vallurupalli, P., Hansen, D., Correia, B., Lange, O., Bah, A., Vernon, R., Dahlquist, F., Baker, D., & Kay, L. (2011) Solution structure of a minor and transiently formed state of a T4 lysozyme mutant. Nature, 477(7362), 111-114. DOI: 10.1038/nature10349
Mulder FA, Mittermaier A, Hon B, Dahlquist FW, & Kay LE. (2001) Studying excited states of proteins by NMR spectroscopy. Nature structural biology, 8(11), 932-5. PMID: 11685237
- June 20, 2011
- 09:14 PM
- 832 views
Alternative side-chain structures from methyl CPMG
by Michael Clarkson in Conformational Flux
As I have mentioned before on this blog, the use of tools like CS-ROSETTA holds the promise of determining protein structures using only the chemical shifts of its backbone atoms. In addition to potentially making NOEs and RDCs redundant, this technology allows biologists to determine the conformations of minor members of the structural ensemble, which are very difficult to obtain using conventional approaches in population-dominated techniques like NMR and X-ray crystallography. There are two l........ Read more »
Hansen, D., Neudecker, P., Vallurupalli, P., Mulder, F., & Kay, L. (2010) Determination of Leu Side-Chain Conformations in Excited Protein States by NMR Relaxation Dispersion. Journal of the American Chemical Society, 132(1), 42-43. DOI: 10.1021/ja909294n
Hansen, D.F., Neudecker, P., & Kay, L.E. (2010) Determination of isoleucine side-chain conformations in ground and excited states of proteins from chemical shifts. Journal of the American Chemical Society, 7589-7591. DOI: 10.1021/ja102090z
Hansen, D.F., & Kay, L.E. (2011) Determining valine side-chain rotamer conformations in proteins from methyl 13C chemical shifts: application to the 360 kDa half-proteasome. Journal of the American Chemical Society, 133(21), 8272-8281. DOI: 10.1021/ja2014532
- April 11, 2011
- 09:58 PM
- 937 views
The classic Alzheimer's aggregates are linked
by Michael Clarkson in Conformational Flux
The classic neuropathological hallmarks of Alzheimer's disease are the appearance of amyloid plaques composed primarily of amyloid beta (Aβ) peptides, and neurofibrillary tangles composed mainly of hyperphosphorylated tau protein. For many years, research into treatments for Alzheimer's disease proceeded on the hypothesis that the plaques were toxic to the surrounding neurons. More recently, however, evidence has shown that soluble Aβ oligomers may be the primary toxic species. A recent paper ........ Read more »
Jin, M., Shepardson, N., Yang, T., Chen, G., Walsh, D., & Selkoe, D. (2011) Soluble amyloid . Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.1017033108
- January 27, 2011
- 03:16 PM
- 588 views
Why HisH doesn't fire until it sees the whites of PRFAR's eyes
by Michael Clarkson in Conformational Flux
The enzyme imidazole glycerophosphate synthase (IGPS) can be a bit of a lump. If you bind just one substrate it doesn't do anything, even though its two active sites are separated by more than 30 Å. Only if the second substrate also binds does catalysis actually go at anything like a respectable rate. In a recent paper in Structure researchers from Yale report evidence that this change of pace results from a change in dynamics.
Apo- IGPS from Thermatoga maritima
PDB code: 1GPW
IGPS consists o........ Read more »
Lipchock, J., & Loria, J. (2010) Nanometer Propagation of Millisecond Motions in V-Type Allostery. Structure, 18(12), 1596-1607. DOI: 10.1016/j.str.2010.09.020
- December 1, 2010
- 07:00 PM
- 740 views
Dynamic origins of PBX1 homeodomain allostery
by Michael Clarkson in Conformational Flux
In the Monod-Wyman-Changeux model for cooperative binding, proteins exist in an equilibrium of low-affinity and high-affinity states in solution, absent any ligand. In this view, although it may appear that the binding of a ligand causes a conformational transition, it actually stabilizes one conformation from a pre-existing equilibrium. In the past several years, advanced NMR techniques have yielded increasing evidence that these structural equilibria exist for a number of proteins, suggesting ........ Read more »
Farber, P., & Mittermaier, A. (2010) Concerted Dynamics Link Allosteric Sites in the PBX Homeodomain. Journal of Molecular Biology. DOI: 10.1016/j.jmb.2010.11.016
- October 11, 2010
- 07:53 PM
- 685 views
Costridium virulence: What's essential?
by Michael Clarkson in Conformational Flux
Clostridium difficile is an intestinal pathogen that causes diarrhea in hospitals and other healthcare settings (including nursing homes). Present as a commensal bacterium in a significant fraction of the population, C. difficile is usually rather harmless, its numbers suppressed by competition with the intestinal flora. When its competitors are decimated by antibiotics, however, C. difficile flourishes, releasing toxins that cause inflammation and diarrhea, which can be dangerous because the in........ Read more »
Kuehne, S., Cartman, S., Heap, J., Kelly, M., Cockayne, A., & Minton, N. (2010) The role of toxin A and toxin B in Clostridium difficile infection. Nature, 467(7316), 711-713. DOI: 10.1038/nature09397
- August 25, 2010
- 08:08 PM
- 668 views
Zombie cyclophilins catalyze HIV capsid isomerization
by Michael Clarkson in Conformational Flux
If you're going to study the role an enzyme plays in a biological pathway, it's often useful to "kill" it with a mutation. For example, the proline cis-trans isomerase cyclophilin A (CypA) needs a particular arginine residue for its chemistry, so mutations that remove or alter that functional group, like R55K and R55A, should destroy the protein's function and have effects on the related pathways that help illustrate its role. The hydrophobic pocket it uses to bind substrates is made by residues........ Read more »
Bosco, D., Eisenmesser, E., Clarkson, M., Wolf-Watz, M., Labeikovsky, W., Millet, O., & Kern, D. (2010) Dissecting the Microscopic Steps of the Cyclophilin A Enzymatic Cycle on the biological substrate HIV-capsid by NMR. Journal of Molecular Biology. DOI: 10.1016/j.jmb.2010.08.001
Saphire, A.C.S., Bobardt, M.D., & Gallay, P.A. (2002) "trans-Complementation Rescue of Cyclophilin A-Deficient Viruses Reveals that the Requirement for Cyclophilin A in Human Immunodeficiency Virus Type 1 Replication Is Independent of Its Isomerase Activity". Journal of Virology, 76(5), 2255-2262. DOI: 10.1128/jvi.76.5.2255-2262.2002
- August 2, 2010
- 08:17 PM
- 692 views
The M2 channel controversy rides again
by Michael Clarkson in Conformational Flux
Most people never learn about an actual scientific controversy. Almost every "controversy" that bubbles into the public eye is manufactured, often reflecting social or ethical differences rather than genuine disagreements between experts about how different models fit to reality. Actual scientific controversies tend to be highly technical, and often concern points that lay people find to be esoteric. That doesn't mean that the issues involved aren't important, or that they're even difficult to u........ Read more »
Andreas, L., Eddy, M., Pielak, R., Chou, J., & Griffin, R. (2010) Magic Angle Spinning NMR Investigation of Influenza A M2 : Support for an Allosteric Mechanism of Inhibition . Journal of the American Chemical Society, 2147483647. DOI: 10.1021/ja101537p
- June 28, 2010
- 08:26 PM
- 772 views
Can oil and water mix?
by Michael Clarkson in Conformational Flux
We all know that linear polymers of amino acids (proteins) adopt complex three-dimensional structures when they are dissolved in water. The process of forming these structures is called folding, and it is understood to occur because proteins are amphiphilic. Some parts of a protein chain like to interact with water (hydrophilic), while others are oily and want to get out of water (hydrophobic). Folding of the chain sticks all the oily parts together on the inside of the structure while the parts........ Read more »
Underwood, R., Tomlinson-Phillips, J., & Ben-Amotz, D. (2010) Are Long-Chain Alkanes Hydrophilic?. The Journal of Physical Chemistry B, 2147483647. DOI: 10.1021/jp912089q
- April 27, 2010
- 10:39 PM
- 1,050 views
Do metamorphic proteins mediate evolutionary structural transitions?
by Michael Clarkson in Conformational Flux
On several previous occasions on this blog I've discussed proteins that undergo significant changes in structure without drastic changes in their primary sequence or solution conditions. In some cases, a few mutations can take a protein to a novel fold, as with Philip Bryan's protein G work. In others, closely related sequences within a whole family populate different kinds of folds, as Matt Cordes illustrated for the case of Cro proteins. In addition, there are some cases such as lymphotactin, ........ Read more »
Yadid, I., Kirshenbaum, N., Sharon, M., Dym, O., & Tawfik, D. (2010) Metamorphic proteins mediate evolutionary transitions of structure. Proceedings of the National Academy of Sciences, 107(16), 7287-7292. DOI: 10.1073/pnas.0912616107
- April 13, 2010
- 08:17 PM
- 846 views
Take cisplatin in the morning and call me
by Michael Clarkson in Conformational Flux
Although we are most familiar with the circadian rhythm from its effects on our physiological state, the roots of the phenomenon lie in the molecular biology of individual cells. The circadian rhythm is the result of a transcriptional control system that regulates the levels of many different proteins in the cell with the passing of time. Not all of the proteins subject to this control have yet been catalogued, and as a result some surprising effects are still being discovered. A recent article ........ Read more »
Kang, T., Lindsey-Boltz, L., Reardon, J., & Sancar, A. (2010) Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase. Proceedings of the National Academy of Sciences, 107(11), 4890-4895. DOI: 10.1073/pnas.0915085107
- March 23, 2010
- 06:00 PM
- 943 views
How native-like is a cold-denatured structure?
by Michael Clarkson in Conformational Flux
A protein has several different levels of structure. The primary structure is the arrangements of atoms and bonds, and it is formed in the ribosome by the assembly of amino acids as directed by an RNA template. The secondary structure is the local topology, the helices and strands, and this forms mostly because of the release of energy through the formation of hydrogen bonds. The tertiary structure is the actual fold of the protein, the way helices, strands, and loops are arranged in space. The ........ Read more »
Babu, C., Hilser, V., & Wand, A. (2004) Direct access to the cooperative substructure of proteins and the protein ensemble via cold denaturation. Nature Structural , 11(4), 352-357. DOI: 10.1038/nsmb739
Shan, B., McClendon, S., Rospigliosi, C., Eliezer, D., & Raleigh, D. (2010) The Cold Denatured State of the C-terminal Domain of Protein L9 Is Compact and Contains Both Native and Non-native Structure. Journal of the American Chemical Society, 2147483647. DOI: 10.1021/ja908104s
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