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Conformational Flux
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- March 22, 2010
- 06:00 PM
- 1,039 views
Dynamics conservation in the Ras superfamily
by Michael Clarkson in Conformational Flux
The proposition that general fold architecture is preserved within a family of evolutionarily-related proteins is not controversial. The amino acid sequence of a protein determines its structure, and countless studies have substantiated the idea that proteins with similar sequences will adopt similar folded conformations. Because structure and dynamics are intrinsically linked, one could reasonably assume that many features of a protein's dynamics get conserved along with the fold. A growing num........ Read more »
Raimondi, F., Orozco, M., & Fanelli, F. (2010) Deciphering the Deformation Modes Associated with Function Retention and Specialization in Members of the Ras Superfamily. Structure, 18(3), 402-414. DOI: 10.1016/j.str.2009.12.015
Law, A., Fuentes, E., & Lee, A. (2009) Conservation of Side-Chain Dynamics Within a Protein Family. Journal of the American Chemical Society, 131(18), 6322-6323. DOI: 10.1021/ja809915a
- February 25, 2010
- 10:28 PM
- 662 views
Prion diseases: protein is enough
by Michael Clarkson in Conformational Flux
Spongiform encephalopathies are transmissible diseases that can have a major economic impact on agricultural exports, and pose a significant challenge for surveillance of the food supply. Scientists generally believe that these diseases are transmitted via a self-propagating, aberrant conformation of the prion protein (PrP). This prion hypothesis suggests that PrP alone should be sufficient to cause symptoms or death. If this hypothesis is true, then it should be possible to reproduce the diseas........ Read more »
Wang, F., Wang, X., Yuan, C., & Ma, J. (2010) Generating a Prion with Bacterially Expressed Recombinant Prion Protein. Science, 327(5969), 1132-1135. DOI: 10.1126/science.1183748
- December 16, 2009
- 09:51 PM
- 583 views
A single residue dictates a fold
by Michael Clarkson in Conformational Flux
Anfinsen's dogma — that the amino acid sequence of a protein uniquely determines its structure — naturally leads one to the idea that identity between amino acid sequences means identity between structures. This has proven to be a successful paradigm: sequence similarity reliably predicts structural and functional similarity. Evidence accruing in recent years, however, suggests that for small proteins, at least, this assumption may not be entirely safe. Adding to this view, in a........ Read more »
Alexander, P., He, Y., Chen, Y., Orban, J., & Bryan, P. (2009) From the Cover: A minimal sequence code for switching protein structure and function. Proceedings of the National Academy of Sciences, 106(50), 21149-21154. DOI: 10.1073/pnas.0906408106
- December 11, 2009
- 10:02 AM
- 683 views
Non-native hydrogen bonds mediate structural transitions
by Michael Clarkson in Conformational Flux
A few weeks ago, I wrote that the goal of a structural biology research program ought to be to "characterize the conformation and energy of key, functionally-relevant members of the protein's structural ensemble and identify the pathways between them." The Nature paper last week, among other examples I mentioned in the preceding post, described functionally significant minor members of the native-state ensemble, and this is certainly an area where structural studies are making a l........ Read more »
Gardino, A., Villali, J., Kivenson, A., Lei, M., Liu, C., Steindel, P., Eisenmesser, E., Labeikovsky, W., Wolf-Watz, M., Clarkson, M.W.... (2009) Transient Non-native Hydrogen Bonds Promote Activation of a Signaling Protein. Cell, 139(6), 1109-1118. DOI: 10.1016/j.cell.2009.11.022
- December 2, 2009
- 10:30 PM
- 819 views
Alternate structures and catalysis in cyclophilin
by Michael Clarkson in Conformational Flux
Of all the sources of structural variability in proteins, the hardest to pin down is side-chain conformational heterogeneity. Side chains aren't always easy to model into their primary conformation in the first place — you need excellent crystal diffraction or NMR data to do it. Even if you pulled that off, it's not always clear how (or if) side-chain fluctuations relate to a protein's activity. If we carefully examine our data for the faintest signals, however, we can sometimes find evide........ Read more »
Fraser, J., Clarkson, M., Degnan, S., Erion, R., Kern, D., & Alber, T. (2009) Hidden alternative structures of proline isomerase essential for catalysis. Nature, 462(7273), 669-673. DOI: 10.1038/nature08615
- October 26, 2009
- 09:30 PM
- 946 views
The role of dynamics in catalysis
by Michael Clarkson in Conformational Flux
For some enzymes, dynamics on the millisecond timescale play a critical role in catalysis. I don't think this is a particularly controversial or unclear statement, but then, I know what I mean by it. In the process of communication, however, the intended meaning sometimes gets lost or transformed. A statement that addresses an entire catalytic cycle, for instance, might be interpreted as addressing only the chemical step. This seems to have happened in a pair of papers that concern the transfer ........ Read more »
Pisliakov, A., Cao, J., Kamerlin, S., & Warshel, A. (2009) Enzyme millisecond conformational dynamics do not catalyze the chemical step. Proceedings of the National Academy of Sciences, 106(41), 17359-17364. DOI: 10.1073/pnas.0909150106
- September 1, 2009
- 08:40 PM
- 777 views
Proteins stick together when it's crowded
by Michael Clarkson in Conformational Flux
One of the many ways that a living cell does not resemble a test tube is in the degree to which its internal environment is crowded. Cells are crammed full of massive protein complexes, vesicles, organelles, carbohydrates, peptidoglycan, and other assemblies that occupy a great deal of space. The tubes and cuvettes used for biochemical experiments, in contrast, typically contain nothing more than a few proteins and small molecules of interest along with a relatively dilute set of salts and buffe........ Read more »
Batra, J., Xu, K., Qin, S., & Zhou, H. (2009) Effect of Macromolecular Crowding on Protein Binding Stability: Modest Stabilization and Significant Biological Consequences. Biophysical Journal, 97(3), 906-911. DOI: 10.1016/j.bpj.2009.05.032
Phillip, Y., Sherman, E., Haran, G., & Schreiber, G. (2009) Common Crowding Agents Have Only a Small Effect on Protein-Protein Interactions. Biophysical Journal, 97(3), 875-885. DOI: 10.1016/j.bpj.2009.05.026
- August 19, 2009
- 10:00 PM
- 846 views
Filling the donut hole in dynamics
by Michael Clarkson in Conformational Flux
This is the last of my series of posts about the dynamics-focused topical issue of JBNMR. There are plenty of other excellent papers in it, and I encourage you to at least glance over all of them, especially if you're an NMR person.Standard NMR dynamics experiments on isotropically tumbling proteins cover a wide, but not comprehensive, swath of fluctuation timescales. Limited information about motions that take milliseconds or more can be obtained from hydrogen exchange data; the AMORE-HX experi........ Read more »
Farès, C., Lakomek, N., Walter, K., Frank, B., Meiler, J., Becker, S., & Griesinger, C. (2009) Accessing ns–μs side chain dynamics in ubiquitin with methyl RDCs. Journal of Biomolecular NMR, 45(1-2), 23-44. DOI: 10.1007/s10858-009-9354-7
- August 17, 2009
- 09:00 PM
- 722 views
Apparently, the moon hit their eyes like a big pizza pie
by Michael Clarkson in Conformational Flux
This post continues my series about selected articles from the dynamics-focused topical issue of JBNMR.It is helpful, in examining some NMR articles, to understand that NMR spectroscopists have a long and resilient tradition of giving their pulse sequences silly names. You can think of it as the biophysical equivalent of fly geneticist behavior. From the basic COSY and NOESY experiments (pronounced "cozy" and "nosy") to the INEPT spin-echo train, to more complicated pulse trains such as AMNESIA ........ Read more »
Gledhill, J., Walters, B., & Wand, A. (2009) AMORE-HX: a multidimensional optimization of radial enhanced NMR-sampled hydrogen exchange. Journal of Biomolecular NMR. DOI: 10.1007/s10858-009-9357-4
- August 5, 2009
- 10:00 PM
- 970 views
Mesodynamics, field cycling, and SARS: an explanation
by Michael Clarkson in Conformational Flux
Part of the motivation for my previous post about the spectral density was the recent appearance online (and upcoming appearance in print) of my paper in the Journal of Biomolecular NMR, which is open access, so you can open it up from home and read along as I tell you about it. The obscure-sounding title "Mesodynamics in the SARS nucleocapsid measured by NMR field cycling" means that we were able to characterize an interesting fluctuation in a protein from the SARS coronavirus, and that we used........ Read more »
Clarkson, M., Lei, M., Eisenmesser, E., Labeikovsky, W., Redfield, A., & Kern, D. (2009) Mesodynamics in the SARS nucleocapsid measured by NMR field cycling. Journal of Biomolecular NMR. DOI: 10.1007/s10858-009-9347-6
- June 1, 2009
- 11:45 PM
- 987 views
How do adamantane drugs block M2?
by Michael Clarkson in Conformational Flux
Vaccination plays such an important role in our seasonal influenza strategy in part because we don't have many medicines that can be brought to bear on the disease. The neuraminidase inhibitors (specifically Tamiflu) are widely stockpiled, and continue to work for now, but the specter of resistance is already lurking. If these drugs are too widely or too improperly used, there is a good chance that resistance mutations will eventually render these drugs ineffective. Universal drug resistance may........ Read more »
Stouffer, A., Acharya, R., Salom, D., Levine, A., Di Costanzo, L., Soto, C., Tereshko, V., Nanda, V., Stayrook, S., & DeGrado, W. (2008) Structural basis for the function and inhibition of an influenza virus proton channel. Nature, 451(7178), 596-599. DOI: 10.1038/nature06528
Schnell, J., & Chou, J. (2008) Structure and mechanism of the M2 proton channel of influenza A virus. Nature, 451(7178), 591-595. DOI: 10.1038/nature06531
Jing, X., Ma, C., Ohigashi, Y., Oliveira, F., Jardetzky, T., Pinto, L., & Lamb, R. (2008) Functional studies indicate amantadine binds to the pore of the influenza A virus M2 proton-selective ion channel. Proceedings of the National Academy of Sciences, 105(31), 10967-10972. DOI: 10.1073/pnas.0804958105
Pielak, R., Schnell, J., & Chou, J. (2009) Mechanism of drug inhibition and drug resistance of influenza A M2 channel. Proceedings of the National Academy of Sciences, 106(18), 7379-7384. DOI: 10.1073/pnas.0902548106
- April 30, 2009
- 11:00 PM
- 1,049 views
cAMP gives CAP a twist
by Michael Clarkson in Conformational Flux
The catabolite activator protein (CAP), which plays a significant role in telling bacterial metabolism to digest sugars other than glucose, is a classic example of allosteric activation. Binding of the small signaling molecule cyclic AMP (cAMP) switches CAP into an active state that recruits RNA polymerase to certain metabolic genes. The biochemistry of cAMP activation is well understood, but the structural basis is not as clear, because a structure of the inactive protein was not available. Thi........ Read more »
Popovych, N., Tzeng, S., Tonelli, M., Ebright, R., & Kalodimos, C. (2009) Structural basis for cAMP-mediated allosteric control of the catabolite activator protein. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.0900595106
- April 13, 2009
- 10:00 PM
- 1,060 views
Drugs disrupt DHFR dynamics
by Michael Clarkson in Conformational Flux
One of the most-studied cases of the relationship between dynamics and catalysis is the bacterial dihydrofolate reductase (DHFR). DHFR catalyzes the reduction of dihydrofolate to tetrahydrofolate while oxidizing the cofactor nicotinamide adenine dinucleotide phosphate (NADPH). As part of this catalytic process, a region of the protein called the "Met 20 loop" switches from a "closed" state that shields the active site from solvent to an "occluded" state that separates the substrate from the cofa........ Read more »
Mauldin, R., Carroll, M., & Lee, A. (2009) Dynamic Dysfunction in Dihydrofolate Reductase Results from Antifolate Drug Binding: Modulation of Dynamics within a Structural State. Structure, 17(3), 386-394. DOI: 10.1016/j.str.2009.01.005
- March 23, 2009
- 09:00 PM
- 1,546 views
Rare codons give domains time to fold
by Michael Clarkson in Conformational Flux
The ribosome produces proteins by matching tRNA that has been correctly loaded with an amino acid to a codon (triplet of DNA bases) in the mRNA that contains the gene sequence. The triplet code allows 64 combinations of nucleotide bases, but proteins are made from only 20 amino acids (plus a "stop" signal). This means that most amino acids are coded by multiple codons, and hence have multiple tRNAs. Not all codons are created equal, however; in bacteria some codons are found much less frequently........ Read more »
Zhang, G., Hubalewska, M., & Ignatova, Z. (2009) Transient ribosomal attenuation coordinates protein synthesis and co-translational folding. Nature Structural , 16(3), 274-280. DOI: 10.1038/nsmb.1554
- March 16, 2009
- 08:30 PM
- 915 views
A deadly halo in Alzheimer's disease
by Michael Clarkson in Conformational Flux
The observation of plaques composed primarily of amyloid-β (Aβ) peptides in the brains of Alzheimer's patients long ago gave rise to a hypothesis that Aβ was the agent that caused the disease. The plaques themselves, composed of long, insoluble fibrils of Aβ, were believed to cause the synapse loss and nerve death characteristic of the disease, and some data supports this model. However, several experiments have suggested an alternative possibility: that the symptoms of Alzheimer's may be at........ Read more »
Koffie, R., Meyer-Luehmann, M., Hashimoto, T., Adams, K., Mielke, M., Garcia-Alloza, M., Micheva, K., Smith, S., Kim, M., Lee, V.... (2009) Oligomeric amyloid associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proceedings of the National Academy of Sciences, 106(10), 4012-4017. DOI: 10.1073/pnas.0811698106
- March 12, 2009
- 08:30 PM
- 1,411 views
Urea binds to the peptide group
by Michael Clarkson in Conformational Flux
I've mentioned urea and guanidinium (Gdm) before on this blog, usually with reference to questions about their mechanism of action. These small molecules cause proteins to denature, or lose their higher levels of structure and become unfolded chains. The complete unfolding of a protein typically requires a fairly high concentration of denaturant, almost always more than 1M, and the explanation for this is that the denaturant molecules preferentially associate with the polypeptide chain with low ........ Read more »
Lim, W., Rosgen, J., & Englander, S. (2009) Urea, but not guanidinium, destabilizes proteins by forming hydrogen bonds to the peptide group. Proceedings of the National Academy of Sciences, 106(8), 2595-2600. DOI: 10.1073/pnas.0812588106
- March 10, 2009
- 07:30 PM
- 928 views
Activated caspases stick together
by Michael Clarkson in Conformational Flux
In a post last week I mentioned a technique for obtaining the high-resolution structure of a protein inside a living cell, but I also pointed out that this technique was difficult and expensive, and might not be applicable to large proteins. Techniques improve and become more powerful, of course, but you might not want to wait for NMR to catch up to your question. Fortunately, high-resolution in vivo structures may not be necessary if you already have relevant dilute-solution structures of your ........ Read more »
J. Gao, S. S. Sidhu, & J. A. Wells. (2009) Two-state selection of conformation-specific antibodies. Proceedings of the National Academy of Sciences, 106(9), 3071-3076. DOI: 10.1073/pnas.0812952106
- March 5, 2009
- 11:00 PM
- 978 views
High resolution protein structure from a living cell
by Michael Clarkson in Conformational Flux
Virtually everything we know about protein conformation comes from experiments performed in environments that do not resemble the biological context of proteins in action. Our data generally come from solutions that lack the significant array of salts, sugars, and metabolites that fill the cytosol of living cells, and often these data are acquired at a pH far removed from cytosolic. In addition, the dilute solution conditions used in almost all structural biology experiments do not capture the c........ Read more »
Daisuke Sakakibara, Atsuko Sasaki, Teppei Ikeya, Junpei Hamatsu, Tomomi Hanashima, Masaki Mishima, Masatoshi Yoshimasu, Nobuhiro Hayashi, Tsutomu Mikawa, Markus Wälchli.... (2009) Protein structure determination in living cells by in-cell NMR spectroscopy. Nature, 458(7234), 102-105. DOI: 10.1038/nature07814
- February 26, 2009
- 09:00 PM
- 1,447 views
A point mutation remodels a binding interface
by Michael Clarkson in Conformational Flux
Decades of studies involving extensive mutagenesis of proteins and protein domains have impressed on us the idea that the folded tertiary structures of proteins are fairly resilient. While a particular mutation may abolish function by directly ablating a key chemical group, it is rare for a single mutation, or even a group of several mutations, to significantly change the overall conformation of a folded polypeptide chain. When a major change does result, it often takes the form of complete dena........ Read more »
M. R. Evans, P. B. Card, & K. H. Gardner. (2009) ARNT PAS-B has a fragile native state structure with an alternative -sheet register nearby in sequence space. Proceedings of the National Academy of Sciences, 106(8), 2617-2622. DOI: 10.1073/pnas.0808270106
- February 12, 2009
- 07:00 PM
- 1,312 views
Allostery in the CBP KIX domain
by Michael Clarkson in Conformational Flux
Classically, allosteric and cooperative effects have been identified with large complexes of multiple protein subunits, in which the binding of a ligand to one subunit enhances ligand binding in a different subunit. While some features of the models developed to deal with these systems do not translate well to cases of allostery within a single protein or domain, many of their core ideas continue to illuminate these single-subunit systems. In an upcoming paper in the Journal of the American Chem........ Read more »
Sven Brüschweiler, Paul Schanda, Karin Kloiber, Bernhard Brutscher, Georg Kontaxis, Robert Konrat, & Martin Tollinger. (2009) Direct Observation of the Dynamic Process Underlying Allosteric Signal Transmission. Journal of the American Chemical Society, 2147483647. DOI: 10.1021/ja809947w
N. K. Goto, T. Zor, M. Martinez-Yamout, H. J. Dyson, & P. E. Wright. (2002) Cooperativity in Transcription Factor Binding to the Coactivator CREB-binding Protein (CBP). Journal of Biological Chemistry, 277(45), 43168-43174. DOI: 10.1074/jbc.M207660200
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