Detecting transient intermediates in macromolecular binding by paramagnetic NMR

Nature
Junji Iwahara, G Marius Clore

Abstract

Macromolecular complex formation is governed by two opposing constraints of specificity and speed. Kinetic and theoretical considerations suggest that significant rate enhancement can be achieved either by reducing the dimensionality of the search process or by the creation of a short-range attractive potential around the target site. This implies the existence of transient intermediates involving non-specific binding modes. Here we show that intermolecular paramagnetic relaxation enhancement (PRE) provides a means of directly detecting the presence of, and investigating the nature of, low population transient intermediates under equilibrium conditions. Applying this approach, we characterize the search process whereby a sequence-specific transcription factor (the homeodomain of HOXD9) binds to non-cognate DNA sites as a means of enhancing the rate of specific association. The PRE data in the fast exchange regime reveal the presence of transient intermediates formed in a stochastic manner at non-cognate sites whose structure is similar to that of the specific complex. Two distinct search processes involving intra- as well as intermolecular translocations can be delineated. The intermolecular PRE method is general and can be rea...Continue Reading

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Citations

Apr 8, 2011·European Biophysics Journal : EBJ·Cyprian D Cukier, Andres Ramos
Nov 4, 2011·Chromosoma·Timothy J Stasevich, James G McNally
May 10, 2007·Journal of Biomolecular NMR·Lianmei FengJames H Prestegard
Jul 28, 2007·Journal of Biomolecular NMR·X WangF Tian
Aug 9, 2008·Journal of Biomolecular NMR·Gottfried Otting
Aug 10, 2011·Journal of Biomolecular NMR·Soumyasri DasguptaMarcellus Ubbink
Sep 29, 2011·Journal of Biomolecular NMR·Nicolas L FawziG Marius Clore
Aug 19, 2011·Journal of Biomolecular NMR·G Marius Clore
May 29, 2012·Journal of Biomolecular NMR·Ivano BertiniDmitri I Svergun
Oct 10, 2013·Protein & Cell·Conggang LiMaili Liu
Jun 15, 2007·Quarterly Reviews of Biophysics·Olav Schiemann, Thomas F Prisner
Mar 5, 2008·Journal of the American Chemical Society·Yong Zhang, Eric Oldfield
May 15, 2010·Journal of the American Chemical Society·Patrick WalshSimon Sharpe
May 14, 2010·Journal of the American Chemical Society·Tobias MadlMichael Sattler
Sep 9, 2010·Journal of the American Chemical Society·Ivano BertiniDmitri I Svergun
Aug 13, 2011·Journal of the American Chemical Society·Valerie A VillarealRobert T Clubb
Sep 12, 2013·Journal of the American Chemical Society·Tiandi ZhuangLukas K Tamm
Sep 10, 2009·Journal of the American Chemical Society·Rasmus LinserBernd Reif
Aug 6, 2008·Nature Structural & Molecular Biology·Jason Gorman, Eric C Greene
Mar 26, 2010·Physical Chemistry Chemical Physics : PCCP·Bing Wang, Kenneth M Merz
May 25, 2012·Physical Chemistry Chemical Physics : PCCP·Ivano BertiniEnrico Ravera
Aug 30, 2008·Proceedings of the National Academy of Sciences of the United States of America·Young C KimGerhard Hummer
Sep 6, 2008·Proceedings of the National Academy of Sciences of the United States of America·Michaeleen Doucleff, G Marius Clore
Jan 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Nicolas L FawziG Marius Clore
Nov 17, 2010·Proceedings of the National Academy of Sciences of the United States of America·Dana Vuzman, Yaakov Levy
May 11, 2011·Proceedings of the National Academy of Sciences of the United States of America·Yuki Takayama, G Marius Clore
Jul 23, 2013·Proceedings of the National Academy of Sciences of the United States of America·Ashok Sekhar, Lewis E Kay
Nov 26, 2010·The Journal of Biological Chemistry·William E BocikJoel R Tolman

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