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Article: Investigating Dynamic Interdomain Allostery in Pin1.

Peng, Jeffrey W

2015 Volume 7, Issue 2, Page(s) 239–249

Abstract: Signaling proteins often sequester complementary functional sites in separate domains. How do the different domains communicate with one another? An attractive system to address this question is the mitotic regulator, human Pin1 (Lu et al. 1996). Pin-1 ... ...

Abstract	Signaling proteins often sequester complementary functional sites in separate domains. How do the different domains communicate with one another? An attractive system to address this question is the mitotic regulator, human Pin1 (Lu et al. 1996). Pin-1 consists of two tethered domains: a WW domain for substrate binding, and a catalytic domain for peptidyl-prolyl isomerase (PPIase) activity. Pin1 accelerates the cis-trans isomerization of phospho-Ser/Thr-Pro (pS/T-P) motifs within proteins regulating the cell cycle and neuronal development. The early x-ray (Ranganathan et al. 1997; Verdecia et al. 2000) and solution NMR studies (Bayer et al. 2003; Jacobs et al. 2003) of Pin1 indicated inter- and intradomain motion. We became interested in exploring how such motions might affect interdomain communication, using NMR. Our accumulated results indicate substrate binding to Pin1 WW domain changes the intra/inter domain mobility, thereby altering substrate activity in the distal PPIase domain catalytic site. Thus, Pin1 shows evidence of dynamic allostery, in the sense of Cooper and Dryden (Cooper and Dryden 1984). We highlight our results supporting this conclusion, and summarize them via a simple speculative model of conformational selection.
Language	English
Publishing date	2015-04-22
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2486483-3
ISSN	1867-2469 ; 1867-2450
ISSN (online)	1867-2469
ISSN	1867-2450
DOI	10.1007/s12551-015-0171-9
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Article ; Online: A gratuitous β-Lactamase inducer uncovers hidden active site dynamics of the Staphylococcus aureus BlaR1 sensor domain.

Frederick, Thomas E / Peng, Jeffrey W

PloS one

2018 Volume 13, Issue 5, Page(s) e0197241

Abstract: Increasing evidence shows that active sites of proteins have non-trivial conformational dynamics. These dynamics include active site residues sampling different local conformations that allow for multiple, and possibly novel, inhibitor binding poses. Yet, ...

Abstract	Increasing evidence shows that active sites of proteins have non-trivial conformational dynamics. These dynamics include active site residues sampling different local conformations that allow for multiple, and possibly novel, inhibitor binding poses. Yet, active site dynamics garner only marginal attention in most inhibitor design efforts and exert little influence on synthesis strategies. This is partly because synthesis requires a level of atomic structural detail that is frequently missing in current characterizations of conformational dynamics. In particular, while the identity of the mobile protein residues may be clear, the specific conformations they sample remain obscure. Here, we show how an appropriate choice of ligand can significantly sharpen our abilities to describe the interconverting binding poses (conformations) of protein active sites. Specifically, we show how 2-(2'-carboxyphenyl)-benzoyl-6-aminopenicillanic acid (CBAP) exposes otherwise hidden dynamics of a protein active site that binds β-lactam antibiotics. When CBAP acylates (binds) the active site serine of the β-lactam sensor domain of BlaR1 (BlaRS), it shifts the time scale of the active site dynamics to the slow exchange regime. Slow exchange enables direct characterization of inter-converting protein and bound ligand conformations using NMR methods. These methods include chemical shift analysis, 2-d exchange spectroscopy, off-resonance ROESY of the bound ligand, and reduced spectral density mapping. The active site architecture of BlaRS is shared by many β-lactamases of therapeutic interest, suggesting CBAP could expose functional motions in other β-lactam binding proteins. More broadly, CBAP highlights the utility of identifying chemical probes common to structurally homologous proteins to better expose functional motions of active sites.
MeSH term(s)	Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/pharmacology ; Bacterial Proteins/metabolism ; Catalytic Domain ; Escherichia coli ; Ligands ; Metalloendopeptidases/metabolism ; Nuclear Magnetic Resonance, Biomolecular ; Penicillanic Acid/analogs & derivatives ; Penicillanic Acid/chemistry ; Penicillanic Acid/pharmacology ; Protein Conformation ; Staphylococcus aureus ; beta-Lactamases/metabolism
Chemical Substances	Anti-Bacterial Agents ; Bacterial Proteins ; Ligands ; 2-(2'-carboxyphenyl)benzoyl-6-aminopenicillanic acid (14796-35-1) ; Penicillanic Acid (87-53-6) ; BlaR1 protein, Staphylococcus aureus (EC 3.4.24.-) ; Metalloendopeptidases (EC 3.4.24.-) ; beta-Lactamases (EC 3.5.2.6)
Language	English
Publishing date	2018-05-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0197241
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Article ; Online: Mixed Ligand Passivation as the Origin of Near-Unity Emission Quantum Yields in CsPbBr

Ding, Yang / Zhang, Zhuoming / Toso, Stefano / Gushchina, Irina / Trepalin, Vadim / Shi, Kejia / Peng, Jeffrey W / Kuno, Masaru

Journal of the American Chemical Society

2023 Volume 145, Issue 11, Page(s) 6362–6370

Abstract: Key features of syntheses, involving the quaternary ammonium passivation of ... ...

Abstract	Key features of syntheses, involving the quaternary ammonium passivation of CsPbBr
Language	English
Publishing date	2023-03-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.2c13527
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Article ; Online: Characterizing Protein Dynamics with NMR R

Massi, Francesca / Peng, Jeffrey W

Methods in molecular biology (Clifton, N.J.)

2017 Volume 1688, Page(s) 205–221

Abstract: The measurement of ... ...

Abstract	The measurement of R
MeSH term(s)	Magnetic Resonance Spectroscopy/methods ; Models, Molecular ; Motion ; Protein Conformation ; Proteins/chemistry ; Thermodynamics
Chemical Substances	Proteins
Language	English
Publishing date	2017-11-17
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-7386-6_10
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Article: NMR Relaxation Dispersion Reveals Macrocycle Breathing Dynamics in a Cyclodextrin-based Rotaxane

Stoffel, Shannon / Zhang, Qi-Wei / Li, Dong-Hao / Smith, Bradley D / Peng, Jeffrey W

Journal of the American Chemical Society. 2020 Mar. 26, v. 142, no. 16

2020

Abstract: A distinctive feature of mechanically interlocked molecules (MIMs) is the relative motion between the mechanically bonded components, and often it is the functional basis for artificial molecular machines and new functional materials. Optimization of ... ...

Abstract	A distinctive feature of mechanically interlocked molecules (MIMs) is the relative motion between the mechanically bonded components, and often it is the functional basis for artificial molecular machines and new functional materials. Optimization of machine or materials performance requires knowledge of the underlying atomic-level mechanisms that control the motion. The field of biomolecular NMR spectroscopy has developed a diverse set of pulse schemes that can characterize molecular dynamics over a broad time scale, but these techniques have not yet been used to characterize the motion within MIMs. This study reports the first observation of NMR relaxation dispersion related to MIM motion. The rotary (pirouette) motion of α-cyclodextrin (αCD) wheels was characterized in a complementary pair of rotaxanes with pirouetting switched ON or OFF. ¹³C and ¹H NMR relaxation dispersion measurements reveal previously unknown exchange dynamics for the αCD wheels in the pirouette-ON rotaxane with a rate constant of 2200 s–¹ at 298 K and an activation barrier of ΔF‡ = 43 ± 3 kJ/mol. The exchange dynamics disappear in the pirouette-OFF rotaxane, demonstrating their switchable nature. The ¹³C and ¹H sites exhibiting relaxation dispersion suggest that the exchange involves “macrocycle breathing”, in which the αCD wheel fluctuates between a contracted or expanded state, the latter enabling diffusive rotary motion about the axle. The substantial insight from these NMR relaxation dispersion methods suggests similar dynamic NMR methods can illuminate the fast time scale (microsecond to millisecond) mechanisms of intercomponent motion in a wide range of MIMs.
Keywords	alpha-cyclodextrin ; carbon ; molecular dynamics ; nuclear magnetic resonance spectroscopy ; rotaxanes ; stable isotopes
Language	English
Dates of publication	2020-0326
Size	p. 7413-7424.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.9b12524
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Article ; Online: Propagated Perturbations from a Peripheral Mutation Show Interactions Supporting WW Domain Thermostability.

Zhang, Meiling / Case, David A / Peng, Jeffrey W

Structure (London, England : 1993)

2018 Volume 26, Issue 11, Page(s) 1474–1485.e5

Abstract: Inter-residue interactions stabilize protein folds and facilitate allosteric communication. Predicting which interactions are crucial and understanding why remain challenging. We highlight this through studies of a single peripheral mutation (Q33E) on ... ...

Abstract	Inter-residue interactions stabilize protein folds and facilitate allosteric communication. Predicting which interactions are crucial and understanding why remain challenging. We highlight this through studies of a single peripheral mutation (Q33E) on the surface of the Pin1 WW domain that causes an unexpected loss of thermostability. Nuclear magnetic resonance studies attribute the loss to reorganizations of electrostatic and hydrophobic interactions, resulting in propagated conformational perturbations. The propagation demonstrates the cooperative response of Pin1 WW to external perturbations, consistent with its allosteric behavior within Pin1. Microsecond molecular dynamics simulations suggest the wild-type fold relies on couplings between a surface electrostatic network and a highly conserved hydrophobic core; Q33E directly perturbs the former, thereby disrupting the latter. These couplings suggest that predictions of mutation consequences that assume dominance of a single interaction type can be limiting, and highlight challenges in predicting protein mutational landscapes.
MeSH term(s)	Allosteric Regulation ; Humans ; Molecular Dynamics Simulation ; Mutation ; NIMA-Interacting Peptidylprolyl Isomerase/chemistry ; NIMA-Interacting Peptidylprolyl Isomerase/genetics ; Protein Binding ; Protein Conformation ; Protein Folding ; Protein Stability ; Thermodynamics ; WW Domains
Chemical Substances	NIMA-Interacting Peptidylprolyl Isomerase ; PIN1 protein, human (EC 5.2.1.8)
Language	English
Publishing date	2018-09-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2018.07.014
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Article: Communication breakdown: protein dynamics and drug design.

Peng, Jeffrey W

Structure (London, England : 1993)

2009 Volume 17, Issue 3, Page(s) 319–320

Abstract: Mauldin et al. (2009) use NMR to show that drug binding can break up collective protein motions necessary for function. We discuss their findings in the context of drug discovery in pharmaceutical research. ...

Abstract	Mauldin et al. (2009) use NMR to show that drug binding can break up collective protein motions necessary for function. We discuss their findings in the context of drug discovery in pharmaceutical research.
MeSH term(s)	Binding Sites ; Drug Design ; Folic Acid Antagonists/chemistry ; Nuclear Magnetic Resonance, Biomolecular ; Structure-Activity Relationship ; Tetrahydrofolate Dehydrogenase/chemistry ; Tetrahydrofolate Dehydrogenase/metabolism
Chemical Substances	Folic Acid Antagonists ; Tetrahydrofolate Dehydrogenase (EC 1.5.1.3)
Language	English
Publishing date	2009-03-11
Publishing country	United States
Document type	Comment ; News
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2009.02.004
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Article ; Online: NMR Relaxation Dispersion Reveals Macrocycle Breathing Dynamics in a Cyclodextrin-based Rotaxane.

Stoffel, Shannon / Zhang, Qi-Wei / Li, Dong-Hao / Smith, Bradley D / Peng, Jeffrey W

Journal of the American Chemical Society

2020 Volume 142, Issue 16, Page(s) 7413–7424

Abstract	A distinctive feature of mechanically interlocked molecules (MIMs) is the relative motion between the mechanically bonded components, and often it is the functional basis for artificial molecular machines and new functional materials. Optimization of machine or materials performance requires knowledge of the underlying atomic-level mechanisms that control the motion. The field of biomolecular NMR spectroscopy has developed a diverse set of pulse schemes that can characterize molecular dynamics over a broad time scale, but these techniques have not yet been used to characterize the motion within MIMs. This study reports the first observation of NMR relaxation dispersion related to MIM motion. The rotary (pirouette) motion of α-cyclodextrin (αCD) wheels was characterized in a complementary pair of rotaxanes with pirouetting switched ON or OFF.
MeSH term(s)	Cyclodextrins/chemistry ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular/methods ; Rotaxanes/chemistry
Chemical Substances	Cyclodextrins ; Rotaxanes
Language	English
Publishing date	2020-04-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.9b12524
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Article ; Online: Coupled intra- and interdomain dynamics support domain cross-talk in Pin1.

Zhang, Meiling / Frederick, Thomas E / VanPelt, Jamie / Case, David A / Peng, Jeffrey W

The Journal of biological chemistry

2020 Volume 295, Issue 49, Page(s) 16585–16603

Abstract: The functional mechanisms of multidomain proteins often exploit interdomain interactions, or "cross-talk." An example is human Pin1, an essential mitotic regulator consisting of a Trp-Trp (WW) domain flexibly tethered to a peptidyl-prolyl isomerase ( ... ...

Abstract	The functional mechanisms of multidomain proteins often exploit interdomain interactions, or "cross-talk." An example is human Pin1, an essential mitotic regulator consisting of a Trp-Trp (WW) domain flexibly tethered to a peptidyl-prolyl isomerase (PPIase) domain, resulting in interdomain interactions important for Pin1 function. Substrate binding to the WW domain alters its transient contacts with the PPIase domain via means that are only partially understood. Accordingly, we have investigated Pin1 interdomain interactions using NMR paramagnetic relaxation enhancement (PRE) and molecular dynamics (MD) simulations. The PREs show that apo-Pin1 samples interdomain contacts beyond the range suggested by previous structural studies. They further show that substrate binding to the WW domain simultaneously alters interdomain separation and the internal conformation of the WW domain. A 4.5-μs all-atom MD simulation of apo-Pin1 suggests that the fluctuations of interdomain distances are correlated with fluctuations of WW domain interresidue contacts involved in substrate binding. Thus, the interdomain/WW domain conformations sampled by apo-Pin1 may already include a range of conformations appropriate for binding Pin1's numerous substrates. The proposed coupling between intra-/interdomain conformational fluctuations is a consequence of the dynamic modular architecture of Pin1. Such modular architecture is common among cell-cycle proteins; thus, the WW-PPIase domain cross-talk mechanisms of Pin1 may be relevant for their mechanisms as well.
MeSH term(s)	Apoproteins/chemistry ; Apoproteins/metabolism ; Binding Sites ; Humans ; Magnetic Resonance Spectroscopy ; Molecular Dynamics Simulation ; Mutagenesis ; NIMA-Interacting Peptidylprolyl Isomerase/chemistry ; NIMA-Interacting Peptidylprolyl Isomerase/genetics ; NIMA-Interacting Peptidylprolyl Isomerase/metabolism ; Nitrogen Oxides/chemistry ; Protein Binding ; Protein Structure, Tertiary ; Spin Labels ; Substrate Specificity ; WW Domains
Chemical Substances	Apoproteins ; NIMA-Interacting Peptidylprolyl Isomerase ; Nitrogen Oxides ; Spin Labels ; PIN1 protein, human (EC 5.2.1.8) ; nitroxyl (GFQ4MMS07W)
Language	English
Publishing date	2020-09-22
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA120.015849
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Article ; Online: Enhanced Sampling of Interdomain Motion Using Map-Restrained Langevin Dynamics and NMR: Application to Pin1.

Bouchard, Jill J / Xia, Junchao / Case, David A / Peng, Jeffrey W

Journal of molecular biology

2018 Volume 430, Issue 14, Page(s) 2164–2180

Abstract: Many signaling proteins consist of globular domains connected by flexible linkers that allow for substantial domain motion. Because these domains often serve as complementary functional modules, the possibility of functionally important domain motions ... ...

Abstract	Many signaling proteins consist of globular domains connected by flexible linkers that allow for substantial domain motion. Because these domains often serve as complementary functional modules, the possibility of functionally important domain motions arises. To explore this possibility, we require knowledge of the ensemble of protein conformations sampled by interdomain motion. Measurements of NMR residual dipolar couplings (RDCs) of backbone HN bonds offer a per-residue characterization of interdomain dynamics, as the couplings are sensitive to domain orientation. A challenge in reaching this potential is the need to interpret the RDCs as averages over dynamic ensembles of domain conformations. Here, we address this challenge by introducing an efficient protocol for generating conformational ensembles appropriate for flexible, multi-domain proteins. The protocol uses map-restrained self-guided Langevin dynamics simulations to promote collective, interdomain motion while restraining the internal domain motion to near rigidity. Critically, the simulations retain an all-atom description for facile inclusion of site-specific NMR RDC restraints. The result is the rapid generation of conformational ensembles consistent with the RDC data. We illustrate this protocol on human Pin1, a two-domain peptidyl-prolyl isomerase relevant for cancer and Alzheimer's disease. The results include the ensemble of domain orientations sampled by Pin1, as well as those of a dysfunctional variant, I28A-Pin1. The differences between the ensembles corroborate our previous spin relaxation results that showed weakened interdomain contact in the I28A variant relative to wild type. Our protocol extends our abilities to explore the functional significance of protein domain motions.
MeSH term(s)	Binding Sites ; Humans ; Models, Molecular ; Motion ; Mutation ; NIMA-Interacting Peptidylprolyl Isomerase/chemistry ; NIMA-Interacting Peptidylprolyl Isomerase/genetics ; Nuclear Magnetic Resonance, Biomolecular ; Protein Conformation ; Protein Domains
Chemical Substances	NIMA-Interacting Peptidylprolyl Isomerase ; PIN1 protein, human (EC 5.2.1.8)
Language	English
Publishing date	2018-05-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2018.05.007
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