Dipolar couplings as a probe of molecular dynamics and structure in solution

Tolman, Joel R.

doi:10.1016/s0959-440x(00)00245-1

Cited by 93 publications

(61 citation statements)

References 68 publications

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“…A number of recent applications (Al-Hashimi & Patel, 2002;Bax et al, 2001;Blackledge, 2005;de Alba & Tjandra, 2002;Prestegard et al, 2000;Tolman, 2001;Zhou et al, 1999) have reignited their wide use in application to a broad spectrum of biomolecules. RDCs arise from the interaction of two magnetically active nuclei in the presence of the external magnetic field of an NMR instrument (Bax et al, 2001;Prestegard et al, 2000;Tjandra et al, 1996;Tolman et al, 1995).…”

Section: Residual Dipolar Couplings (Rdcs)mentioning

confidence: 99%

“…They may also be acquired very rapidly and accurately by a number of techniques including, direct measurement of splittings in coupled heteronuclear single quantum coherence spectra (HSQC) (Bax et al, 1994;Bodenhausen & Ruben, 1980;Cavanagh et al, 1995;Tolman & Prestegard, 1996). RDCs provide structural (Bax et al, 2001;Cornilescu et al, 1999;Delaglio et al, 2000) and motional (Al-Hashimi et al, 2002b;Bax, 2003;Bernardo & Blackledge, 2004a, 2004bBlackledge, 2005;Clore & Schwieters, 2003;O'Neil-Cabello et al, 2004;Tolman, 2001;Yi et al, 2004) information in a biologically relevant timescale and have been used in studies of carbohydrates (Adeyeye et al, 2003;Tian et al, 2001a), nucleic acids (Al-Hashimi et al, 2000a, 2002a, 2002bTjandra et al, 2000;Vermeulen et al, 2000) and proteins (Andrec et al, 2001;Assfalg et al, 2003;Bertini et al, 2003;Clore & Bewley, 2002;Cornilescu et al, 1999;Fowler et al, 2000;Tian et al, 2001b). The use of RDCs as the main source of structural information has led to a significant reduction in data collection and analysis, while providing the possibility of simultaneous resonance assignment, structure determination, and identification of dynamical regions (Bernado & Blackledge, 2004b;Prestegard et al, 2005;Shealy et al, 2011;Tian et al, 2001b;…”

Section: Residual Dipolar Couplings (Rdcs)mentioning

confidence: 99%

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Structure and Dynamics of Proteins from Nuclear Magnetic Resonance Spectroscopy

Valafar¹,

Irausquin²

2012

Protein Structure

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Section: Residual Dipolar Couplings (Rdcs)mentioning

confidence: 99%

Section: Residual Dipolar Couplings (Rdcs)mentioning

confidence: 99%

Structure and Dynamics of Proteins from Nuclear Magnetic Resonance Spectroscopy

Valafar¹,

Irausquin²

2012

Protein Structure

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“…This practice has been established to address some limitations of RDC data such as inherent insensitivity to 180° rotations and varying sensitivity as a function of position within the principal alignment frame (PAF) [15,[26][27][28][29]. It is for these reasons that we insist on utilizing RDC data from two alignment media even though data from a single alignment medium may be adequate in some instances.…”

Section: Integration Of Rdc Data From Different Alignment Mediamentioning

confidence: 99%

Rapid classification of protein structure models using unassigned backbone RDCs and probability density profile analysis (PDPA)

Bansal

Miao

Adams

et al. 2008

Journal of Magnetic Resonance

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A method of identifying the best structural model for a protein of unknown structure from a list of structural candidates using unassigned 15 N-1 H residual dipolar coupling (RDC) data and probability density profile analysis (PDPA) is described. Ten candidate structures have been obtained for the structural genomics target protein PF2048.1 using ROBETTA. 15 N-1 H residual dipolar couplings have been measured from NMR spectra of the protein in two alignment media and these data have been analyzed using PDPA to rank the models in terms of their ability to represent the actual structure.A number of advantages in using this method to characterize a protein structure become apparent. RDCs can easily and rapidly be acquired, and without the need for assignment, the cost and duration of data acquisition is greatly reduced. The approach is quite robust with respect to imprecise and missing data. In the case of PF2048.1, a 79 residue protein, only 58 and 55 of the total RDC data were observed. The method can accelerate structure determination at higher resolution using traditional NMR spectroscopy by providing a starting point for the addition of NOEs and other NMR structural data.

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“…on larger proteins [6] and have improved the accuracy of the resulting models [7]. However, the technique's most effective role in the pharmaceutical industry is in lead discovery and validation.…”

mentioning

confidence: 99%

Synergistic Use of Protein Crystallography and Solution‐phase NMR Spectroscopy in Structure‐based Drug Design: Strategies and Tactics

Abad‐Zapatero

Stamper

Stoll

2006

Fragment‐based Approaches in Drug Discovery

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Structural biology is an integral part of the drug discovery process in the pharmaceutical industry. Two complementary methods dominate among the experimental techniques capable of providing detailed three-dimensional (3D) structural information of therapeutically relevant targets, most often with bound ligands: protein crystallography and solution-phase NMR spectroscopy. The structural information these techniques provide continues to grow in depth and breadth, impacting every step of drug discovery from lead identification to preclinical testing ( Fig. 12.1). Used together, protein crystallography and solution-phase NMR can significantly increase both the pace of discovery and the quality of the resulting compounds that are moved forward into development.The benefits to drug discovery of rapidly available, high-resolution 3D structural information provided by protein crystallography are well established [1,2]. While the technique's success depends on diffraction-quality protein crystals, significant advances in protein biochemistry and protein crystallization technologies have dramatically increased the number of targets amenable to structure determination by X-ray diffraction. Driven in large part by a number of worldwide structural genomics efforts underway in both academia and industry [3], these advances include robotic systems for cloning, expression, protein purification and crystallization [4]. In addition, continued hardware and software developments, both at synchrotron and in-house X-ray sources, have decreased the time of de novo structure solution from months to days, while co-crystal structures are routinely obtained within hours. Thus, once diffraction-quality crystals are obtained, structure determination is not a bottleneck in the discovery process. In fact, a number of drugs on the market were discovered in large part by routine use of structural information provided by protein crystallography [2, 5], a clear indication that this technique has become a driver of the design process and not a retrospective analysis tool.In academia, solution-phase NMR spectroscopy continues to develop as a technique for obtaining 3D structural information of macromolecules including target-ligand complexes. Recent advances have made NMR structural work possible 249 Fragment-based Approaches in Drug Discovery. Edited

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Dipolar couplings as a probe of molecular dynamics and structure in solution

Cited by 93 publications

References 68 publications

Structure and Dynamics of Proteins from Nuclear Magnetic Resonance Spectroscopy

Structure and Dynamics of Proteins from Nuclear Magnetic Resonance Spectroscopy

Rapid classification of protein structure models using unassigned backbone RDCs and probability density profile analysis (PDPA)

Synergistic Use of Protein Crystallography and Solution‐phase NMR Spectroscopy in Structure‐based Drug Design: Strategies and Tactics

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