当前位置： SCI文献检索 > JOURNAL OF MOLECULAR BIOLOGY期刊下所有文献 > Monitoring Ligand-Induced Protein Ordering in Drug Discovery.

Monitoring Ligand-Induced Protein Ordering in Drug Discovery.

Abstract：

:While the gene for p53 is mutated in many human cancers causing loss of function, many others maintain a wild-type gene but exhibit reduced p53 tumor suppressor activity through overexpression of the negative regulators, Mdm2 and/or MdmX. For the latter mechanism of loss of function, the activity of endogenous p53 can be restored through inhibition of Mdm2 or MdmX with small molecules. We previously reported a series of compounds based upon the Nutlin-3 chemical scaffold that bind to both MdmX and Mdm2 [Vara, B. A. et al. (2014) Organocatalytic, diastereo- and enantioselective synthesis of nonsymmetric cis-stilbene diamines: A platform for the preparation of single-enantiomer cis-imidazolines for protein-protein inhibition. J. Org. Chem. 79, 6913-6938]. Here we present the first solution structures based on data from NMR spectroscopy for MdmX in complex with four of these compounds and compare them with the MdmX:p53 complex. A p53-derived peptide binds with high affinity (Kd value of 150nM) and causes the formation of an extensive network of hydrogen bonds within MdmX; this constitutes the induction of order within MdmX through ligand binding. In contrast, the compounds bind more weakly (Kd values from 600nM to 12μM) and induce an incomplete hydrogen bond network within MdmX. Despite relatively weak binding, the four compounds activated p53 and induced p21(Cip1) expression in retinoblastoma cell lines that overexpress MdmX, suggesting that they specifically target MdmX and/or Mdm2. Our results document structure-activity relationships for lead-like small molecules targeting MdmX and suggest a strategy for their further optimization in the future by using NMR spectroscopy to monitor small-molecule-induced protein order as manifested through hydrogen bond formation.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Grace CR,Ban D,Min J,Mayasundari A,Min L,Finch KE,Griffiths L,Bharatham N,Bashford D,Kiplin Guy R,Dyer MA,Kriwacki RW

doi

10.1016/j.jmb.2016.01.016

subject

Has Abstract

pub_date

2016-03-27 00:00:00

pages

1290-1303

issue

6

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(16)00035-8

journal_volume

428

pub_type

杂志文章

相关文献

JOURNAL OF MOLECULAR BIOLOGY文献大全
  • Electron microscopy of decorated crystals for the determination of crystallographic rotation and translation parameters in large protein complexes.

    abstract：:The lumazine synthase/riboflavin synthase complex of Bacillus subtilis consists of an icosahedral capsid of 60 beta subunits enclosing a core of 3 alpha subunits. The preparation of reconstituted hollow capsids consisting of 60 beta subunits and their crystallization in a hexagonal (space group P6(3)22) and in a monoc...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/0022-2836(92)90105-s

    authors： Bacher A,Weinkauf S,Bachmann L,Ritsert K,Baumeister W,Huber R,Ladenstein R

    更新日期：1992-06-20 00:00:00

  • Structure and reactivity of an asymmetric complex between HslV and I-domain deleted HslU, a prokaryotic homolog of the eukaryotic proteasome.

    abstract：:In the prokaryotic homolog of the eukaryotic proteasome, HslUV, the "double donut" HslV protease is allosterically activated by HslU, an AAA protein of the Clp/Hsp100 family consisting of three (amino-terminal, carboxy-terminal, and intermediate) domains. The intermediate domains of HslU, which extend like tentacles f...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/s0022-2836(03)00580-1

    authors： Kwon AR,Kessler BM,Overkleeft HS,McKay DB

    更新日期：2003-07-04 00:00:00

  • Genetic selection for critical residues in ribonucleases.

    abstract：:Homologous mammalian proteins were subjected to an exhaustive search for residues that are critical to their structure/function. Error-prone polymerase chain reactions were used to generate random mutations in the genes of bovine pancreatic ribonuclease (RNase A) and human angiogenin, and a genetic selection based on ...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2006.07.020

    authors： Smith BD,Raines RT

    更新日期：2006-09-22 00:00:00

  • An algorithm for the prediction of proteasomal cleavages.

    abstract：:Proteasomes, major proteolytic sites in eukaryotic cells, play an important part in major histocompatibility class I (MHC I) ligand generation and thus in the regulation of specific immune responses. Their cleavage specificity is of outstanding interest for this process. In order to generalize previously determined cl...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1006/jmbi.2000.3683

    authors： Kuttler C,Nussbaum AK,Dick TP,Rammensee HG,Schild H,Hadeler KP

    更新日期：2000-05-05 00:00:00

  • Intermonomer hydrogen bonds enhance GxxxG-driven dimerization of the BNIP3 transmembrane domain: roles for sequence context in helix-helix association in membranes.

    abstract：:We determined the sequence dependence of human BNIP3 transmembrane domain dimerization using the biological assay TOXCAT. Mutants in which intermonomer hydrogen bonds between Ser172 and His173 are abolished show moderate interaction, indicating that side-chain hydrogen bonds contribute to dimer stability but are not e...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2009.12.023

    authors： Lawrie CM,Sulistijo ES,MacKenzie KR

    更新日期：2010-03-05 00:00:00

  • A ligand-centric analysis of the diversity and evolution of protein-ligand relationships in E.coli.

    abstract：:As enzymes evolve and diverge from common ancestor sequences, they often keep their overall reaction chemistry but specialize in the binding of different cognate ligands. This study borrows methods for the computational assessment of 2D similarity of small molecules from the field of chemoinformatics, to examine the e...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2005.01.061

    authors： Nobeli I,Spriggs RV,George RA,Thornton JM

    更新日期：2005-03-25 00:00:00

  • Relative flexibility of DNA and RNA: a molecular dynamics study.

    abstract：:State of the art molecular dynamics simulations are used to study the structure, dynamics, molecular interaction properties and flexibility of DNA and RNA duplexes in aqueous solution. Special attention is paid to the deformability of both types of structures, revisiting concepts on the relative flexibility of DNA and...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2004.07.048

    authors： Noy A,Pérez A,Lankas F,Javier Luque F,Orozco M

    更新日期：2004-10-22 00:00:00

  • Kinetic stability and crystal structure of the viral capsid protein SHP.

    abstract：:SHP, the capsid-stabilizing protein of lambdoid phage 21, is highly resistant against denaturant-induced unfolding. We demonstrate that this high functional stability of SHP is due to a high kinetic stability with a half-life for unfolding of 25 days at zero denaturant, while the thermodynamic stability is not unusual...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2004.09.030

    authors： Forrer P,Chang C,Ott D,Wlodawer A,Plückthun A

    更新日期：2004-11-12 00:00:00

  • Reconstituted and native iron-cores of bacterioferritin and ferritin.

    abstract：:The structural and magnetic properties of the iron-cores of reconstituted horse spleen ferritin and Azotobacter vinelandii bacterioferritin have been investigated by high-resolution transmission electron microscopy, electron diffraction and Mossbauer spectroscopy. The structural properties of native horse spleen ferri...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/0022-2836(87)90290-7

    authors： Mann S,Williams JM,Treffry A,Harrison PM

    更新日期：1987-12-05 00:00:00

  • Characterization of the C-terminal DNA-binding/DNA endonuclease region of a group II intron-encoded protein.

    abstract：:Group II intron retrohoming occurs by a mechanism in which the intron RNA reverse splices directly into one strand of a double-stranded DNA target site, while the intron-encoded reverse transcriptase uses a C-terminal DNA endonuclease activity to cleave the opposite strand and then uses the cleaved 3' end as a primer ...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/s0022-2836(02)01147-6

    authors： San Filippo J,Lambowitz AM

    更新日期：2002-12-13 00:00:00

  • Inter-domain motions of the N-domain of the KdpFABC complex, a P-type ATPase, are not driven by ATP-induced conformational changes.

    abstract：:P-type ATPases are involved in the active transport of ions across biological membranes. The KdpFABC complex (P-type ATPase) of Escherichia coli is a high-affinity K+ uptake system that operates only when the cell experiences osmotic stress or K+ limitation. Here, we present the solution structure of the nucleotide bi...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2004.07.060

    authors： Haupt M,Bramkamp M,Coles M,Altendorf K,Kessler H

    更新日期：2004-10-01 00:00:00

  • The secondary structure of the von Willebrand factor type A domain in factor B of human complement by Fourier transform infrared spectroscopy. Its occurrence in collagen types VI, VII, XII and XIV, the integrins and other proteins by averaged structure pr

    abstract：:The type A domain of the von Willebrand Factor is found also in the complement proteins factor B (FB), C2, CR3 and CR4, the integrins, collagen types VI, VII, XII and XIV, and other proteins. FB is a component of the alternative pathway of the complement system of immune defence, and is cleaved into the fragments Bb a...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1006/jmbi.1994.1271

    authors： Perkins SJ,Smith KF,Williams SC,Haris PI,Chapman D,Sim RB

    更新日期：1994-04-22 00:00:00

  • β-Structure within the Denatured State of the Helical Protein Domain BBL.

    abstract：:Protein denatured states are the origin of both healthy and toxic conformational species. Denatured states of ultrafast folding proteins are of interest in mechanistic studies because they are energetically close to the kinetic bottleneck of folding. However, their transient nature makes them elusive to experiment. He...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2015.08.007

    authors： Thukral L,Schwarze S,Daidone I,Neuweiler H

    更新日期：2015-09-25 00:00:00

  • Antifreeze protein from freeze-tolerant grass has a beta-roll fold with an irregularly structured ice-binding site.

    abstract：:The grass Lolium perenne produces an ice-binding protein (LpIBP) that helps this perennial tolerate freezing by inhibiting the recrystallization of ice. Ice-binding proteins (IBPs) are also produced by freeze-avoiding organisms to halt the growth of ice and are better known as antifreeze proteins (AFPs). To examine th...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2012.01.032

    authors： Middleton AJ,Marshall CB,Faucher F,Bar-Dolev M,Braslavsky I,Campbell RL,Walker VK,Davies PL

    更新日期：2012-03-09 00:00:00

  • Amyloidogenic propensities and conformational properties of ProIAPP and IAPP in the presence of lipid bilayer membranes.

    abstract：:Human islet amyloid polypeptide (hIAPP), which is considered the primary culprit for beta-cell loss in type 2 diabetes mellitus patients, is synthesized in beta-cells of the pancreas from its precursor pro-islet amyloid polypeptide (proIAPP), which may be important in early intracellular amyloid formation as well. We ...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2009.04.077

    authors： Jha S,Sellin D,Seidel R,Winter R

    更新日期：2009-06-26 00:00:00

  • Effects of calcium binding on the side-chain methyl dynamics of calbindin D9k: a 2H NMR relaxation study.

    abstract：:The effects of Ca(2+) binding on the side-chain methyl dynamics of calbindin D(9k) have been characterized by (2)H NMR relaxation rate measurements. Longitudinal, transverse in-phase, quadrupolar order, transverse anti-phase and double quantum relaxation rates are reported for both the apo and Ca(2+)-loaded states of ...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2006.01.031

    authors： Johnson E,Chazin WJ,Rance M

    更新日期：2006-04-07 00:00:00

  • Extensive microheterogeneity of serine tRNA genes from Drosophila melanogaster.

    abstract：:The nucleotide sequences of nine genes corresponding to tRNA(Ser)4 or tRNA(Ser)7 of Drosophila melanogaster were determined. Eight of the genes compose the major tRNA(Ser)4,7 cluster at 12DE on the X chromosome, while the other is from 23E on the left arm of chromosome 2. Among the eight X-linked genes, five different...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/0022-2836(87)90553-5

    authors： Cribbs DL,Leung J,Newton CH,Hayashi S,Miller RC Jr,Tener GM

    更新日期：1987-10-05 00:00:00

  • Bacterial repression loops require enhanced DNA flexibility.

    abstract：:The Escherichia coli lac operon provides a classic paradigm for understanding regulation of gene transcription. It is now appreciated that lac promoter repression involves cooperative binding of the bidentate lac repressor tetramer to pairs of lac operators via DNA looping. We have adapted components of this system to...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2005.04.035

    authors： Becker NA,Kahn JD,Maher LJ 3rd

    更新日期：2005-06-17 00:00:00

  • Impact of mutations on the allosteric conformational equilibrium.

    abstract：:Allostery in a protein involves effector binding at an allosteric site that changes the structure and/or dynamics at a distant, functional site. In addition to the chemical equilibrium of ligand binding, allostery involves a conformational equilibrium between one protein substate that binds the effector and a second s...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2012.11.041

    authors： Weinkam P,Chen YC,Pons J,Sali A

    更新日期：2013-02-08 00:00:00

  • Human liver cathepsin D. Purification, crystallization and preliminary X-ray diffraction analysis of a lysosomal enzyme.

    abstract：:The two-chain form of active cathepsin D, a glycosylated, lysosomal aspartic proteinase, has been isolated from human liver. Isoelectric focusing revealed two major species of enzyme that differed by approximately 0.2 pI unit. Crystals suitable for X-ray diffraction analysis were prepared from acidic solutions using p...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/0022-2836(92)90696-h

    authors： Gulnik S,Baldwin ET,Tarasova N,Erickson J

    更新日期：1992-09-05 00:00:00

  • Mutation spectrum following transfection of ultraviolet-irradiated single-stranded or double-stranded shuttle vector DNA into monkey cells.

    abstract：:We designed a shuttle vector system that allowed a comparison of the mutation spectrum on the supF target gene after transfection of single-stranded or double-stranded DNA into monkey cells. Single-strand-derived plasmids exhibited a spontaneous mutation frequency tenfold higher than double-strand-derived ones. These ...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/0022-2836(91)90252-2

    authors： Madzak C,Sarasin A

    更新日期：1991-04-20 00:00:00

  • HMMSTR: a hidden Markov model for local sequence-structure correlations in proteins.

    abstract：:We describe a hidden Markov model, HMMSTR, for general protein sequence based on the I-sites library of sequence-structure motifs. Unlike the linear hidden Markov models used to model individual protein families, HMMSTR has a highly branched topology and captures recurrent local features of protein sequences and struc...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1006/jmbi.2000.3837

    authors： Bystroff C,Thorsson V,Baker D

    更新日期：2000-08-04 00:00:00

  • Crystallization and preliminary X-ray diffraction results of trichorzianine A 1, a peptide with nineteen residues from Trichoderma harzianum.

    abstract：:Trichorzianine A 1 is one of the main components of a mixture of related antibiotic peptides (trichorzianines) produced by the fungus Trichoderma harzianum. Good crystals were obtained and allowed X-ray diffraction up to 0.8 A resolution. The space group is orthorhombic, C222(1), Z = 8, a = 64.8 (1) A, b = 9.33 (3) A,...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/s0022-2836(83)80133-8

    authors： Bachet B,Brassy C,Morize I,Surcouf E,Mornon JP,Bodo B,Rebuffat S

    更新日期：1983-11-05 00:00:00

  • Evolution of an interloop disulfide bond in high-affinity antibody mimics based on fibronectin type III domain and selected by yeast surface display: molecular convergence with single-domain camelid and shark antibodies.

    abstract：:The 10th human fibronectin type III domain ((10)Fn3) is one of several protein scaffolds used to design and select families of proteins that bind with high affinity and specificity to macromolecular targets. To date, the highest affinity (10)Fn3 variants have been selected by mRNA display of libraries generated by ran...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2007.02.029

    authors： Lipovsek D,Lippow SM,Hackel BJ,Gregson MW,Cheng P,Kapila A,Wittrup KD

    更新日期：2007-05-11 00:00:00

  • Structural analysis of yeast HSF by site-specific crosslinking.

    abstract：:We have introduced cysteine substitutions into the yeast HSF1 gene at a variety of locations. Most have no phenotypic effect, and therefore provide site-specific probes for thiol-specific reagents. Crosslinking of single mutants identifies locations where equivalent regions of individual monomers can approach each oth...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1006/jmbi.2000.4096

    authors： Bonner JJ,Chen D,Storey K,Tushan M,Lea K

    更新日期：2000-09-22 00:00:00

  • Structural evidence for effectiveness of darunavir and two related antiviral inhibitors against HIV-2 protease.

    abstract：:No drug has been targeted specifically for HIV-2 (human immunodeficiency virus type 2) infection despite its increasing prevalence worldwide. The antiviral HIV-1 (human immunodeficiency virus type 1) protease (PR) inhibitor darunavir and the chemically related GRL98065 and GRL06579A were designed with the same chemica...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2008.09.031

    authors： Kovalevsky AY,Louis JM,Aniana A,Ghosh AK,Weber IT

    更新日期：2008-12-05 00:00:00

  • The homologous pairing domain of RecA also mediates the allosteric regulation of DNA binding and ATP hydrolysis: a remarkable concentration of functional residues.

    abstract：:Switching between the active (ATP and DNA bound) and inactive conformations of the homologous recombination RecA protein is regulated by ATP hydrolysis. First, we use the homologous pairing domain of RecA derived from its mobile loop L2 to show that the interaction of this random coil peptide with the gamma-phosphate ...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1006/jmbi.2000.4163

    authors： Voloshin ON,Wang L,Camerini-Otero RD

    更新日期：2000-11-10 00:00:00

  • Tau factor from Escherichia coli mediates accurate and efficient termination of transcription at the bacteriophage T3 early termination site in vitro.

    abstract：:The termination signal that limits transcription through the early region of bacteriophage T3 (T3Te) has been cloned and sequenced. The nucleotide sequence of T3Te is identical with that of T7Te, with the exception of a single G to U substitution in the 3' tail of the terminated transcript, and addition of an AC to th...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/0022-2836(87)90456-6

    authors： Briat JF,Bollag G,Kearney CA,Molineux I,Chamberlin MJ

    更新日期：1987-11-05 00:00:00

  • Antisense-RNA mediated transcriptional attenuation: importance of a U-turn loop structure in the target RNA of plasmid pIP501 for efficient inhibition by the antisense RNA.

    abstract：:Antisense-RNA mediated gene regulation has been found and studied in detail mainly in prokaryotic accessory DNA elements. In spite of different regulatory mechanisms, in all cases a rapid interaction between antisense and target RNA has been shown to be crucial for efficient regulation. Recently, a sequence comparison...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/j.jmb.2003.09.020

    authors： Heidrich N,Brantl S

    更新日期：2003-11-07 00:00:00

  • Three-dimensional structure and substrate binding of Bacillus stearothermophilus neopullulanase.

    abstract：:Crystal structures of Bacillus stearothermophilus TRS40 neopullulanase and its complexes with panose, maltotetraose and isopanose were determined at resolutions of 1.9, 2.4, 2.8 and 3.2A, respectively. Since the latter two carbohydrates are substrates of this enzyme, a deactivated mutant at the catalytic residue Glu35...

    journal_title：Journal of molecular biology

    pub_type： 杂志文章

    doi：10.1016/s0022-2836(02)01402-x

    authors： Hondoh H,Kuriki T,Matsuura Y

    更新日期：2003-02-07 00:00:00