scholarly journals The osmolyte trimethylamine-N -oxide stabilizes the Fyn SH3 domain without altering the structure of its folding transition state

2009 ◽  
Vol 18 (3) ◽  
pp. 526-536 ◽  
Author(s):  
Sung Lun Lin ◽  
Arash Zarrine-Afsar ◽  
Alan R. Davidson
Keyword(s):  
Transition State ◽  
Sh3 Domain

scholarly journals Conserved patterns and interactions in the unfolding transition state across SH3 domain structural homologues

2020 ◽  
Vol 30 (2) ◽  
pp. 391-407
Author(s):  
Cullen Demakis ◽  
Matthew C. Childers ◽  
Valerie Daggett
Keyword(s):  
Transition State ◽  
Sh3 Domain ◽  
Structural Homologues

Transition state of a SH3 domain detected with principle component analysis and a charge-neutralized all-atom protein model

2006 ◽  
Vol 64 (4) ◽  
pp. 883-894 ◽  
Author(s):  
Daisuke Mitomo ◽  
Hironori K. Nakamura ◽  
Kazuyoshi Ikeda ◽  
Akihiko Yamagishi ◽  
Junichi Higo
Keyword(s):  
Transition State ◽  
Principle Component Analysis ◽  
Component Analysis ◽  
Sh3 Domain ◽  
Principle Component ◽  
Protein Model ◽  
A Charge

scholarly journals Nucleation and the Transition State of the SH3 Domain

2005 ◽  
Vol 349 (2) ◽  
pp. 424-434 ◽  
Author(s):  
Isaac A. Hubner ◽  
Katherine A. Edmonds ◽  
Eugene I. Shakhnovich
Keyword(s):  
Transition State ◽  
Sh3 Domain

scholarly journals Force-dependent switch in protein unfolding pathways and transition-state movements

2016 ◽  
Vol 113 (6) ◽  
pp. E715-E724 ◽  
Author(s):  
Pavel I. Zhuravlev ◽  
Michael Hinczewski ◽  
Shaon Chakrabarti ◽  
Susan Marqusee ◽  
D. Thirumalai
Keyword(s):  
Transition State ◽  
Single Molecule ◽  
Single Point ◽  
Optical Tweezer ◽  
Sh3 Domain ◽  
Single Domain ◽  
Structural Basis ◽  
Single Point Mutation ◽  
Single Chain ◽  
Upward Curvature

Although it is known that single-domain proteins fold and unfold by parallel pathways, demonstration of this expectation has been difficult to establish in experiments. Unfolding rate, ku(f), as a function of force f, obtained in single-molecule pulling experiments on src SH3 domain, exhibits upward curvature on a log⁡ku(f) plot. Similar observations were reported for other proteins for the unfolding rate ku([C]). These findings imply unfolding in these single-domain proteins involves a switch in the pathway as f or [C] is increased from a low to a high value. We provide a unified theory demonstrating that if log⁡ku as a function of a perturbation (f or [C]) exhibits upward curvature then the underlying energy landscape must be strongly multidimensional. Using molecular simulations we provide a structural basis for the switch in the pathways and dramatic shifts in the transition-state ensemble (TSE) in src SH3 domain as f is increased. We show that a single-point mutation shifts the upward curvature in log⁡ku(f) to a lower force, thus establishing the malleability of the underlying folding landscape. Our theory, applicable to any perturbation that affects the free energy of the protein linearly, readily explains movement in the TSE in a β-sandwich (I27) protein and single-chain monellin as the denaturant concentration is varied. We predict that in the force range accessible in laser optical tweezer experiments there should be a switch in the unfolding pathways in I27 or its mutants.

Important role of hydrogen bonds in the structurally polarized transition state for folding of the src SH3 domain

10.1038/1412 ◽  
1998 ◽  
Vol 5 (8) ◽  
pp. 714-720 ◽  
Author(s):  
Viara P. Grantcharova ◽  
David S. Riddle ◽  
Jed V. Santiago ◽  
David Baker
Keyword(s):  
Hydrogen Bonds ◽  
Transition State ◽  
Sh3 Domain

Hydrophobic core packing in the SH3 domain folding transition state

2002 ◽  
Vol 9 (2) ◽  
pp. 126-130 ◽  
Author(s):  
Julian G.B. Northey ◽  
Ariel A. Di Nardo ◽  
Alan R. Davidson
Keyword(s):  
Transition State ◽  
Sh3 Domain ◽  
Hydrophobic Core ◽  
Core Packing

Memapsin 2, a drug target for Alzheimer's disease

2003 ◽  
Vol 70 ◽  
pp. 213-220 ◽  
Author(s):  
Gerald Koelsch ◽  
Robert T. Turner ◽  
Lin Hong ◽  
Arun K. Ghosh ◽  
Jordan Tang
Keyword(s):  
Crystal Structure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transition State ◽  
Amyloid Precursor Protein ◽  
Therapeutic Target ◽  
Drug Target ◽  
Aspartic Protease ◽  
Precursor Protein ◽  
Memapsin 2

Mempasin 2, a ϐ-secretase, is the membrane-anchored aspartic protease that initiates the cleavage of amyloid precursor protein leading to the production of ϐ-amyloid and the onset of Alzheimer's disease. Thus memapsin 2 is a major therapeutic target for the development of inhibitor drugs for the disease. Many biochemical tools, such as the specificity and crystal structure, have been established and have led to the design of potent and relatively small transition-state inhibitors. Although developing a clinically viable mempasin 2 inhibitor remains challenging, progress to date renders hope that memapsin 2 inhibitors may ultimately be useful for therapeutic reduction of ϐ-amyloid.

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