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Lee, Chewook,Ham, Sihyun Wiley Subscription Services, Inc., A Wiley Company 2011 Journal of computational chemistry Vol.32 No.2
<P><B>Abstract</B></P><P>Extracellular deposition of amyloid‐beta (Aβ) protein, a fragment of membrane glycoprotein called β‐amyloid precursor transmembrane protein (βAPP), is the major characteristic for the Alzheimer's disease (AD). However, the structural and mechanistic information of forming Aβ protein aggregates in a lag phase in cell exterior has been still limited. Here, we have performed multiple all‐atom molecular dynamics simulations for physiological 42‐residue amyloid‐beta protein (Aβ42) in explicit water to characterize most plausible aggregation‐prone structure (APS) for the monomer and the very early conformational transitions for Aβ42 protein misfolding process in a lag phase. Monitoring the early sequential conformational transitions of Aβ42 misfolding in water, the APS for Aβ42 monomer is characterized by the observed correlation between the nonlocal backbone H‐bond formation and the hydrophobic side‐chain exposure. Characteristics on the nature of the APS of Aβ42 allow us to provide new insight into the higher aggregation propensity of Aβ42 over Aβ40, which is in agreement with the experiments. On the basis of the structural features of APS, we propose a plausible aggregation mechanism from APS of Aβ42 to form fibril. The structural and mechanistic observations based on these simulations agree with the recent NMR experiments and provide the driving force and structural origin for the Aβ42 aggregation process to cause AD. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2011</P>
Understanding pre-structured motifs (PreSMos) in intrinsically unfolded proteins.
Lee, Si-Hyung,Kim, Do-Hyoung,Han, Joan J,Cha, Eun-Ji,Lim, Ji-Eun,Cho, Ye-Jin,Lee, Chewook,Han, Kyou-Hoon Bentham Science Publishers 2012 Current protein & peptide science Vol.13 No.1
<P>Intrinsically unfolded proteins (IUPs) do not obey the golden rule of structural biology, 3D structure = function, as they manifest their inherent functions without resorting to three-dimensional structures. Absence of a compact globular topology in these proteins strongly implies that their ligand recognition processes should involve factors other than spatially well-defined binding pockets. Heteronuclear multidimensional (HetMulD) NMR spectroscopy assisted with a stable isotope labeling technology is a powerful tool for quantitatively investigating detailed structural features in IUPs. In particular, it allows us to delineate the presence and locations of pre-structured motifs (PreSMos) on a per-residue basis. PreSMos are the transient local structural elements that presage target-bound conformations and act as specificity determinants for IUP recognition by target proteins. Here, we present a brief chronicle of HetMulD NMR studies on IUPs carried out over the past two decades along with a discussion on the functional significance of PreSMos in IUPs.</P>
Structural investigation on the intrinsically disordered N-terminal region of HPV16 E7 protein
( Chewook Lee ),( Do Hyoung Kim ),( Si Hyung Lee ),( Jiulong Su ),( Kyou Hoon Han ) 생화학분자생물학회(구 한국생화학분자생물학회) 2016 BMB Reports Vol.49 No.8
Human papillomavirus (HPV) is the major cause of cervical cancer, a deadly threat to millions of females. The early oncogene product (E7) of the high-risk HPV16 is the primary agent associated with HPV-related cervical cancers. In order to understand how E7 contributes to the transforming activity, we investigated the structural features of the flexible N-terminal region (46 residues) of E7 by carrying out N-15 heteronuclear NMR experiments and replica exchange molecular dynamics simulations. Several NMR parameters as well as simulation ensemble structures indicate that this intrinsically disordered region of E7 contains two transient (10-20% populated) helical pre-structured motifs that overlap with important target binding moieties such as an E2F-mimic motif and a pRb-binding LXCXE segment. Presence of such target-binding motifs in HPV16 E7 provides a reasonable explanation for its promiscuous target-binding behavior associated with its transforming activity. [BMB Reports 2016; 49(8): 431-436]
Rescuing p53 from mdm2 by a pre-structured motif in intrinsically unfolded SUMO specific protease 4
( Do-hyoung Kim ),( Chewook Lee ),( Bom Kim ),( Si-hyung Lee ),( Kyou-hoon Han ) 생화학분자생물학회(구 한국생화학분자생물학회) 2017 BMB Reports Vol.50 No.10
Many intrinsically unstructured/unfolded proteins (IUPs) contain transient local secondary structures even though they are “unstructured” in a tertiary sense. These local secondary structures are named “pre-structured motifs (PreSMos)” and in fact are the specificity determinants for IUP-target binding, i.e., the active sites in IUPs. Using high-resolution NMR we have delineated a PreSMo active site in the intrinsically unfolded mid-domain (residues 201-300) of SUMO-specific protease 4 (SUSP4). This 29-residue motif which we termed a p53 rescue motif can protect p53 from mdm2 quenching by binding to the p53-helix binding pocket in mdm2(3-109). Our work demonstrates that the PreSMo approach is quite effective in providing a structural rationale for interactions of p53-mdm2-SUSP4 and opens a novel avenue for designing mdm2-inhibiting anticancer compounds. [BMB Reports: Perspective 2017; 50(10): 485-486]
Elucidating the Molecular Origin of Hydrolysis Energy of Pyrophosphate in Water
Hong, Jooyeon,Yoshida, Norio,Chong, Song-Ho,Lee, Chewook,Ham, Sihyun,Hirata, Fumio American Chemical Society 2012 Journal of chemical theory and computation Vol.8 No.7
<P>The molecular origin of the energy produced by the ATP hydrolysis has been one of the long-standing fundamental issues. A classical view is that the negative hydrolysis free energy of ATP originates from intramolecular effects connected with the backbone P–O bond, so called “high-energy bond”. On the other hand, it has also been recognized that solvation effects are essential in determining the hydrolysis free energy. Here, using the 3D-RISM-SCF (three-dimensional reference interaction site model self-consistent field) theory that integrates the <I>ab initio</I> quantum chemistry method and the statistical mechanical theory of liquids, we investigate the molecular origin of hydrolysis free energy of pyrophosphate, an ATP analogue, in water. We demonstrate that our theory quantitatively reproduces the experimental results without the use of empirical parameters. We clarify the crucial role of water in converting the hydrolysis free energy in the gas phase determined solely by intramolecular effects, which ranges from endothermic, thermoneutral, to highly exothermic depending on the charged state of pyrophosphate, into moderately exothermic in the aqueous phase irrespective of the charged state as observed in experimental data. We elucidate that this is brought about by different natures of solute–water interactions depending on the charged state of solute species: the hydration free energy of low-charged state is mainly subjected to short-range hydrogen-bonds, while that of high-charged state is dominated by long-range electrostatic interactions. We thus provide unambiguous evidence on the critical role of water in determining the ATP hydrolysis free energy.</P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ct300099e'>ACS Electronic Supporting Info</A></P>
( Peter Tompa ),( Kyou-hoon Han ),( Monika Bokor ),( Pawel Kamasa ),( Agnes Tantos ),( Beata Fritz ),( Do-hyoung Kim ),( Chewook Lee ),( Tamas Verebelyi ),( Kalman Tompa ) 생화학분자생물학회(구 한국생화학분자생물학회) 2016 BMB Reports Vol.49 No.9
Wide-line ¹H NMR intensity and differential scanning calorimetry measurements were carried out on the intrinsically disordered 73-residue full transactivation domain (TAD) of the p53 tumor suppressor protein and two peptides: one a wild type p53 TAD peptide with a helix pre-structuring property, and a mutant peptide with a disabled helix-forming propensity. Measurements were carried out in order to characterize their water and ion binding characteristics. By quantifying the number of hydrate water molecules, we provide a microscopic description for the interactions of water with a wild-type p53 TAD and two p53 TAD peptides. The results provide direct evidence that intrinsically disordered proteins (IDPs) and a less structured peptide not only have a higher hydration capacity than globular proteins, but are also able to bind a larger amount of charged solute ions. [BMB Reports 2016; 49(9): 497-501]