Abstract:
:Protein flexibility is thought to play key roles in numerous biological processes, including antibody affinity maturation, signal transduction, and enzyme catalysis, yet only limited information is available regarding the molecular details linking protein dynamics with function. A single point mutation at the distal site of the endogenous tissue inhibitor of metalloproteinase 1 (TIMP-1) enables this clinical target protein to tightly bind and inhibit membrane type 1 matrix metalloproteinase (MT1-MMP) by increasing only the association constant. The high-resolution X-ray structure of this complex determined at 2 A could not explain the mechanism of enhanced binding and pointed to a role for protein conformational dynamics. Molecular dynamics (MD) simulations reveal that the high-affinity TIMP-1 mutants exhibit significantly reduced binding interface flexibility and more stable hydrogen bond networks. This was accompanied by a redistribution of the ensemble of substrates to favorable binding conformations that fit the enzyme catalytic site. Apparently, the decrease in backbone flexibility led to a lower entropy cost upon formation of the complex. This work quantifies the effect of a single point mutation on the protein conformational dynamics and function of TIMP-1. Here we argue that controlling the intrinsic protein dynamics of MMP endogenous inhibitors may be utilized for rationalizing the design of selective novel protein inhibitors for this class of enzymes.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Grossman M,Tworowski D,Dym O,Lee MH,Levy Y,Murphy G,Sagi Idoi
10.1021/bi902141xsubject
Has Abstractpub_date
2010-07-27 00:00:00pages
6184-92issue
29eissn
0006-2960issn
1520-4995journal_volume
49pub_type
杂志文章相关文献
BIOCHEMISTRY文献大全abstract::A systematic 220-MHz proton nuclear magnetic resonance (nmr) study has been made of all common purine and pyrimidine 2'(3')-ribonucleotides in D2O solutions at 20 plus or minus 2 degrees. Spectra for the entire series were measured under similar conditions of concentration, temperature, and ionic strength, thereby fac...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00674a013
更新日期:1975-02-11 00:00:00
abstract::Acid beta-glucosidase is a lysosomal membrane protein that cleaves the O-beta-D-glucosidic linkage of glucosylceramide and aryl-beta-glucosides. Full activity reconstitution of the pure enzyme requires phospholipids and saposin C, an 80 aa activator protein. The deficiency of the enzyme or activator leads to Gaucher d...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi980785+
更新日期:1998-08-18 00:00:00
abstract::Crystallographic analysis revealed that the nicotinamide ring of NAD can bind with multiconformations to aldehyde dehydrogenase (ALDH) (Ni, L., Zhou, J., Hurley, T. D., and Weiner, H. (1999) Protein Sci. 8, 2784-2790). Electron densities can be defined for two conformations, neither of which appears to be compatible w...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi012197t
更新日期:2002-06-04 00:00:00
abstract::The outer mitochondrial membrane isoform of mammalian cytochrome b(5) (OM b(5)) is distinguished from the microsomal isoform (Mc b(5)) by its considerably greater stability. In contrast, OM and Mc apocytochrome b(5) (apo-b(5)) exhibit similar thermodynamic stability. Contributing substantially to the greater stability...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi051337m
更新日期:2005-11-08 00:00:00
abstract::Information on the secondary structure and interactions of RNA is important to understand the biological function of RNA as well as in applying RNA as a tool for therapeutic purposes. Recently, the isoenergetic microarray mapping method was developed to improve the prediction of RNA secondary structure. Herein, for th...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi200463p
更新日期:2011-09-06 00:00:00
abstract::Multiple forms of the acute-phase serum protein SAA were isolated from the lipoprotein fraction of plasma from a single individual. These protein forms were purified by size-exclusion, ion-exchange, and reverse-phase high-pressure liquid chromatography, and then the tryptic peptides were subjected to amino acid sequen...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00405a044
更新日期:1988-03-08 00:00:00
abstract::The aminolysis of the depsipeptide m-[[(phenylacetyl)glycyl]oxy]benzoic acid (1) by D-phenylalanine, catalyzed by the beta-lactamase of Enterobacter cloacae P99, is inhibited by the product of the reaction, (phenylacetyl)glycyl-D-phenylalanine (2), by the peptide analogue of 1, m-[(phenylacetyl)-glycinamido]benzoic ac...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00443a015
更新日期:1989-08-22 00:00:00
abstract::Bacterial bioluminescence is a phenomenon resulting from the reaction of a two-component FMN-dependent aldehyde monooxygenase system, which comprises a bacterial luciferase and a flavin reductase. Bacterial luciferase (LuxAB) is one of the most extensively investigated two-component monooxygenases, while its reductase...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi1009985
更新日期:2010-11-02 00:00:00
abstract::Inexpensive, straightforward, and rapid medical diagnostics are becoming increasingly important for disease identification in time- and resource-limited settings. Previous attempts to link oligonucleotide-based aptamers and hammerhead ribozymes to form ligand-induced ribozymes have been successful in identifying a var...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/acs.biochem.8b00523
更新日期:2018-08-28 00:00:00
abstract::The bacterial alpha-lytic protease (alphaLP) is synthesized as a precursor containing a large N-terminal pro region (Pro) transiently required for correct folding of the protease [Silen, J. L., and Agard, D. A. (1989) Nature 341, 462-464]. Upon folding, the precursor is autocatalyticly cleaved to yield a tight-binding...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi982165e
更新日期:1999-04-13 00:00:00
abstract::The diiron active sites of the purple acid phosphatases from porcine uterus (also called uteroferrin, Uf) and bovine spleen (BSPAP) and their complexes with tungstate are compared by 1H NMR and NOE techniques. The paramagnetically shifted features of the 1H NMR spectrum of reduced BSPAP are similar to those of reduced...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00138a004
更新日期:1992-06-16 00:00:00
abstract::Alpha2u-globulin is a male rat liver protein under multihormonal control which represents approximately 1% of hepatic protein synthesis. We have measured the rate of transcription of the alpha2u-globulin gene using a nuclear cell-free transcriptional system with mercurated CTP as substrate for the endogenous RNA polym...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00608a023
更新日期:1978-07-25 00:00:00
abstract::Biochemical properties of a detergent-solubilized tetrodotoxin binding component from Electrophorus electricus have been examined and compared with those found for the membrane-bound protein. The toxin binding component was solubilized with high efficiency by a variety of nonionic detergents and with lower efficiency ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00267a029
更新日期:1982-11-23 00:00:00
abstract::Anastellin is a small recombinant fragment derived from the extracellular matrix protein fibronectin; it comprises the first type III (FN3) domain without the two N-terminal β-strands. It inhibits angiogenesis, tumor growth, and metastasis in mouse models and requires endogenous fibronectin for its in vivo anti-angiog...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/acs.biochem.7b00633
更新日期:2017-09-05 00:00:00
abstract::Inwardly rectifying potassium channels are important in cellular repolarization of many excitable tissues. Amino acid sequence alignment of different mammalian inward rectifier K(+) channels revealed two absolutely conserved cysteine residues in the putative extracellular face, suggesting a possible disulfide bond. Re...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi992469g
更新日期:2000-04-25 00:00:00
abstract::Human immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2, respectively) exhibit extensive genetic variations. It was postulated that much of this genetic variability stems from the low fidelity of the reverse transcription step. Both HIV reverse transcriptases (RTs) were shown to be particularly error-prone during...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00154a010
更新日期:1992-10-06 00:00:00
abstract::Venomous organisms have evolved a variety of structurally diverse peptide neurotoxins that target ion channels. Despite the lack of any obvious structural homology, unrelated toxins that interact with voltage-activated K(+) channels share a dyad motif composed of a lysine and a hydrophobic amino acid residue, usually ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi0495681
更新日期:2004-07-13 00:00:00
abstract::In prokaryotes, a large share of the proteins are secreted from the cell through a process that requires their translocation across the cytoplasmic membrane. This process is mediated by the universally conserved Sec system with homologues in the endoplasmic reticulum and thylakoid membranes of eukaryotes. The Sec syst...
journal_title:Biochemistry
pub_type: 杂志文章,评审
doi:10.1021/bi400913x
更新日期:2013-10-01 00:00:00
abstract::Fluorescent nucleobase analogues are used extensively to probe the structure and dynamics of nucleic acids. The fluorescence of the adenine analogue 2-aminopurine and the cytosine analogue pyrrolocytosine is significantly quenched when the bases are located in regions of double-stranded nucleic acids. To allow more de...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi060479t
更新日期:2006-08-01 00:00:00
abstract::The ratio of the second-order rate constants for reduction of dihydroxyacetone phosphate (DHAP) and of the neutral truncated substrate glycolaldehyde (GLY) by glycerol 3-phosphate dehydrogenase (NAD (+), GPDH) saturated with NADH is (1.0 x 10 (6) M (-1) s (-1))/(8.7 x 10 (-3) M (-1) s (-1)) = 1.1 x 10 (8), which was u...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi8001743
更新日期:2008-04-22 00:00:00
abstract::We have obtained the 470 MHz 19F NMR spectra of wild type [4-F]Trp-labeled myoglobins (MbCO, MbO2, deoxyMb, metMb, and MbCN) and hemoglobins (HbCO, HbO2, and deoxyHb), as well as those of several mutants (W7F Mb, betaW15F Hb, betaW37S Hb, and betaY130F Hb, all as the carbonmonoxy adducts), prepared via site-directed m...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi961664h
更新日期:1997-03-25 00:00:00
abstract::The proton nuclear magnetic resonance spectrum of human adult deoxyhemoglobin in D2O in the region from 6 to 20 ppm downfield from the proton resonance of residual water shows a number of hyperfine shifted proton resonances that are due to groups on or near the alpha and beta hemes. The sensitivity of these resonances...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00590a031
更新日期:1979-11-13 00:00:00
abstract::In a previously determined minimal kinetic scheme for DNA polymerization catalyzed by the Klenow fragment (KF) of Escherichia coli DNA polymerase I, a nonchemical step that interconverted the KF'.DNAn+1.PPi and KF.DNAn+1PPi complexes was not observed in correct incorporation [Kuchta, R. D., Mizrahi, V., Benkovic, P.A....
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00234a002
更新日期:1991-05-21 00:00:00
abstract::Although the Escherichia coli fatty acid synthesis (FAS) pathway is the best studied type II fatty acid synthesis system, a major experimental limitation has been the inability to feed intermediates into the pathway in vivo because exogenously supplied free fatty acids are not efficiently converted to the acyl-acyl ca...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi901890a
更新日期:2010-02-02 00:00:00
abstract::Myelin basic protein (MBP) is a multifunctional protein involved in maintaining the stability and integrity of the myelin sheath by a variety of interactions with membranes and with cytoskeletal and other proteins. A central segment of MBP is highly conserved in mammals and consists of a membrane surface-associated am...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi701336n
更新日期:2008-01-08 00:00:00
abstract::JZTX-XI is a peptide toxin isolated from the venom of the Chinese spider Chilobrachys jingzhao. It contains 34 residues including six cysteine residues with disulfide bridges linked in the pattern of I-IV, II-V, and III-VI. Using 3'- and 5'-RACE methods, the full-length cDNA was identified as encoding an 86-residue pr...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi061457+
更新日期:2006-12-26 00:00:00
abstract::Chemoenzymatic glycan remodeling by endoglycosidase-catalyzed deglycosylation and reglycosylation is emerging as an attractive approach for producing homogeneous glycoforms of antibodies, and the success of this approach depends on the discovery of efficient endoglycosidases and their glycosynthase mutants. We report ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/acs.biochem.8b00719
更新日期:2018-09-04 00:00:00
abstract::Atomic resolution ( journal_title:Biochemistry pub_type: 杂志文章 doi:10.1021/bi0517133 更新日期:2006-02-21 00:00:00
abstract::Actinaria cytolysins are very potent basic toxins isolated from the venom of sea anemones, which are supposed to exert their toxic activity through formation of oligomeric pores in the host plasma membrane. To gain insight into their mechanism of action, the interaction of Stichodactyla helianthus sticholysin I (St-I)...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi960787z
更新日期:1996-11-26 00:00:00
abstract::Measurements of the magnetic field dependence of the longitudinal magnetic relaxation rates (NMRD profiles) of solvent protons and deuterons led to the discovery of two classes of solvent binding sites in Ca2+-Mn2+-concanavalin A (CMPL) [Koenig, S. H., Brown, R. D., III, & Brewer, C. F. (1985) Biochemistry (second of ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00340a004
更新日期:1985-09-10 00:00:00