Abstract：
:Human angiotensin-converting enzyme (ACE) has two homologous domains, the N and C domains, with differing substrate preferences. X-ray crystal structures of the C and N domains complexed with various inhibitors have allowed identification of active site residues that might be important for the molecular basis of this selectivity. However, it is unclear to what extent the different residues contribute to substrate domain selectivity. Here, cocrystal structures of human testis ACE, equivalent to the C domain, have been determined with two novel C domain-selective ketomethylene inhibitors, (5 S)-5-[( N-benzoyl)amino]-4-oxo-6-phenylhexanoyl- l-tryptophan (kAW) and (5 S)-5-[( N-benzoyl)amino]-4-oxo-6-phenylhexanoyl- l-phenylalanine (kAF). The ketone groups of both inhibitors bind to the zinc ion as a hydrated geminal diolate, demonstrating the ability of the active site to catalyze the formation of the transition state. Moreover, active site residues involved in inhibitor binding have been mutated to their N domain counterparts, and the effect of the mutations on inhibitor binding has been determined. The C domain selectivity of these inhibitors was found to result from interactions between bulky hydrophobic side chain moieties and C domain-specific residues F391, V518, E376, and V380 (numbering of testis ACE). Mutation of these residues decreased the affinity for the inhibitors 4-20-fold. T282, V379, E403, D453, and S516 did not contribute individually to C domain-selective inhibitor binding. Further domain-selective inhibitor design should focus on increasing both the affinity and selectivity of the side chain moieties.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Watermeyer JM,Kröger WL,O'Neill HG,Sewell BT,Sturrock EDdoi
10.1021/bi8002605subject
Has Abstractpub_date
2008-06-03 00:00:00pages
5942-50issue
22eissn
0006-2960issn
1520-4995journal_volume
47pub_type
杂志文章相关文献
BIOCHEMISTRY文献大全abstract：:A heparin-induced conformational change is required to convert antithrombin from a slow to a fast inhibitor of factor Xa. It has been proposed [van Boeckel et al. (1994) Nat. Struct. Biol. 1, 423-425] that the reactive center residue P14 is inserted into beta-sheet A in native antithrombin and is displaced from the be...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi9604643
更新日期：1996-07-02 00:00:00
abstract：:A conformational transition is described for the polypeptide, gramicidin A, in which a dimer that forms a left-handed intertwined antiparallel helix is converted to a single-stranded amino terminus to amino terminus right-handed helix. The starting structure is determined here by solution NMR methods while reference i...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi00152a019
更新日期：1992-09-22 00:00:00
abstract：:The R2 protein of ribonucleotide reductase catalyzes the dioxygen-dependent one-electron oxidation of Tyr122 at a diiron-carboxylate site. Methane monooxygenase and related hydroxylases catalyze hydrocarbon hydroxylation at diiron sites structurally related to the one in R2. In protein R2, the likely reaction site for...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi9806403
更新日期：1998-07-28 00:00:00
abstract：:Interleukin-8 (IL-8), a member of the chemokine superfamily, exists as both monomers and dimers, and mediates its function by binding to neutrophil CXCR1 and CXCR2 receptors that belong to the G protein-coupled receptor class. It is now well established that the monomer functions as a high-affinity ligand, but the bin...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi0605944
更新日期：2006-06-27 00:00:00
abstract：:The crystal structure of Escherichia coli GAR Tfase at 2.1 A resolution in complex with 10-formyl-5,8,10-trideazafolic acid (10-formyl-TDAF, K(i) = 260 nM), an inhibitor designed to form an enzyme-assembled multisubstrate adduct with the substrate, beta-GAR, was studied to determine the exact nature of its inhibitory ...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi991888a
更新日期：1999-12-21 00:00:00
abstract：:We have used [(1)H-(15)N]-HSQC NMR to investigate the structural changes that occur in both serpin and proteinase in forming the kinetically trapped covalent protein-protein complex that is the basis for serpin inhibition of serine proteinases. By alternately using (15)N-alanine specifically-labeled alpha(1)-proteinas...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi010100x
更新日期：2001-05-29 00:00:00
abstract：:Plasma membrane and vesicular transporters for the biogenic amines, dopamine, norepinephrine, and serotonin, represent a group of proteins that play a crucial role in the regulation of neurotransmission. Clinically, mono amine transporters are the primary targets for the actions of many therapeutic agents used to trea...
journal_title：Biochemistry
pub_type： 杂志文章,评审
doi：10.1021/bi200405c
更新日期：2011-08-30 00:00:00
abstract：:A small metal-binding protein (SmbP) with no known similarity to other proteins in current databases was isolated and characterized from the periplasm of Nitrosomonas europaea. The primary structure of this small (9.9 kDa) monomeric protein is characterized by a series of 10 repeats of a seven amino acid motif and an ...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi049318k
更新日期：2004-09-07 00:00:00
abstract：:Epigallocatechin-3-gallate (EGCG) is a catechin found in green tea that can inhibit the amyloid formation of a wide variety of proteins. EGCG's ability to prevent or redirect the amyloid formation of so many proteins may reflect a common mechanism of action, and thus, greater molecular-level insight into how it exerts...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/acs.biochem.0c00043
更新日期：2020-03-17 00:00:00
abstract：:Extracellular cAMP induces the rapid activation of guanylate cyclase, which adapts within 10 s to constant cAMP concentrations. A new response can be induced either by a higher cAMP concentration or by the same cAMP concentration at some time (t1/2 = 90 s) after removal of the previous stimulus. Stimulation of guanyla...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi00397a047
更新日期：1987-11-17 00:00:00
abstract：:The formation of ternary complexes involving serine proteases, borate, and an alcohol has important implications for understanding the physiological actions of borate and for the development of tight binding inhibitors for this class of enzymes. Recent studies of a related enzyme, gamma-glutamyl transpeptidase, which ...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi025583z
更新日期：2002-05-14 00:00:00
abstract：:Immunoglobulins fragments are composed of globular domains linked by extended polypeptide segments. The molecular flexibility inherent in this arrangement allows for significant potential differences between structures observed in the crystalline state and those attained in solution. Small-angle neutron scattering mea...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi00541a011
更新日期：1982-06-08 00:00:00
abstract：:Thyroperoxidase (TPO), a type I transmembrane heme containing glycoprotein, catalyzes iodide organification and thyroid hormone synthesis. One of the two main alternatively spliced forms of this enzyme, TPOzanelli, which is present in Graves's disease thyroid tissue, has a cytoplasmic domain completely modified. In th...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi0026324
更新日期：2001-02-27 00:00:00
abstract：:We have measured the hydration of CO2 catalyzed by bovine red cell carbonic anhydrase in mixtures of H2O and D2O at pH(D) which is in the plateau region of the pH--activity profile. The steady-state parameters for hydration Vmax and Km both show an exponential dependence on the atom fraction of deuterium in solvent wa...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi00563a008
更新日期：1980-10-28 00:00:00
abstract：:To characterize the role of water in protein-DNA interactions, we have studied the specificity of the EcoRI restriction endonuclease as a function of osmotic and hydrostatic pressure. The extent of cleavage by the enzyme at noncanonical ("star") sites is shown to depend uniquely upon the osmotic pressure in the reacti...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi00179a001
更新日期：1994-04-05 00:00:00
abstract：:Resonance Raman spectra of the photosynthetic reaction center isolated from the green bacterium Chloroflexus aurantiacus have been obtained with excitation in the near-infrared absorption bands of the special pair (P) and the accessory bacteriochlorophyll (B) using shifted-excitation Raman difference spectroscopy (SER...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi00015a044
更新日期：1995-04-18 00:00:00
abstract：:Triple helix-forming oligonucleotides (TFOs) bind with high affinity and specificity to homopurine-homopyrimidine sequences in DNA and have been shown to inhibit transcription of target genes in various experimental systems. In the present study, we evaluated the ability of 3'-amino-modified phosphodiester TFOs direct...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi992185w
更新日期：2000-05-02 00:00:00
abstract：:Haloalkane dehalogenase converts haloalkanes to their corresponding alcohols and halides. The reaction mechanism involves the formation of a covalent alkyl-enzyme complex which is hydrolyzed by water. The active site is a hydrophobic cavity buried between the main domain and the cap domain of the enzyme. The enzyme ha...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi952904g
更新日期：1996-05-07 00:00:00
abstract：:The X-ray structures of the ligand free (apo) and the Mg(2+)*o-succinylbenzoate (OSB) product complex of o-succinylbenzoate synthase (OSBS) from Escherichia coli have been solved to 1.65 and 1.77 A resolution, respectively. The structure of apo OSBS was solved by multiple isomorphous replacement in space group P2(1)2(...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi000855o
更新日期：2000-09-05 00:00:00
abstract：:Biogenesis of pyrroloquinoline quinone (PQQ) in Klebsiella pneumoniae requires the expression of six genes (pqqA-F). One of these genes (pqqE) encodes a 43 kDa protein (PqqE) that plays a role in the initial steps in PQQ formation [Veletrop, J. S., et al. (1995) J. Bacteriol. 177, 5088-5098]. PqqE contains two highly ...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi900918b
更新日期：2009-10-27 00:00:00
abstract：:Time-resolved infrared (TRIR) techniques have been employed to study the reactions of carbon monoxide with the cytochrome alpha 3-Cu(B) site of cytochrome c oxidase (CcO). The ligation dynamics immediately following photodissociation have been investigated using picosecond TRIR spectroscopy and linear dichroism. The r...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi00168a015
更新日期：1994-01-18 00:00:00
abstract：:All eight cysteine residues, C90, C94, C143, C147, C219, C325, C367, and C431, present in transmembrane domains of the Aspergillus nidulans NrtA nitrate transporter protein were altered individually by site-specific mutagenesis. The results indicate that six residues, C90, C147, C219, C325, C367, and C431, are not req...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi047732e
更新日期：2005-04-12 00:00:00
abstract：:The factors that govern the substrate reactivity and stereoselectivity of phosphotriesterase (PTE) toward organophosphotriesters containing various combinations of methyl, ethyl, isopropyl, and phenyl substituents at the phosphorus center were determined by systematic alterations in the dimensions of the active site. ...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi001549d
更新日期：2001-02-06 00:00:00
abstract：:Gastric parietal cell apical membranes must protect the cell from the extremely low pH and wide variations in osmolality of the gastric juice. To characterize the permeability properties of gastric apical membranes, we have measured passive permeabilities to water, protons, NH3, and small nonelectrolytes of membrane v...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi00061a002
更新日期：1993-03-16 00:00:00
abstract：:IFABP is a small beta-barrel protein with a short helix-turn-helix motif near the N-terminus that is thought to participate in the regulation of the uptake and delivery of fatty acids. In a previous work, we detected by near UV circular dichroism a reversible conformational transition of this protein occurring between...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi020680d
更新日期：2003-06-24 00:00:00
abstract：:After extensive studies spanning over half a century, there is little consensus on the kinetic mechanism of DNA polymerases. Using stopped-flow fluorescence assays for mammalian DNA polymerase beta (Pol beta), we have previously identified a fast fluorescence transition corresponding to conformational closing, and a s...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi700084w
更新日期：2007-05-08 00:00:00
abstract：:The association of nucleolar phosphoprotein C23 with preribosomal ribonucleoprotein (RNP) particles was examined in Novikoff hepatoma nucleoli. RNA was labeled with [3H]uridine for various times in cell suspensions, and RNP particles were extracted from isolated nucleoli and fractionated by sucrose gradient ultracentr...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi00368a063
更新日期：1986-10-07 00:00:00
abstract：:Catalase (hydroperoxidase) HPII of Escherichia coli is the largest catalase so far characterized, existing as a homotetramer of 84 kDa subunits. Each subunit has a core structure that closely resembles small subunit catalases, supplemented with an extended N-terminal sequence and compact flavodoxin-like C-terminal dom...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi034208j
更新日期：2003-05-20 00:00:00
abstract：:The ability of a class of C-20' modified vinca alkaloid congeners to induce tubulin spiral formation was investigated relative to their ability to inhibit microtubule assembly, their cytotoxicity against a leukemic cell line, L1210, and their measured and calculated partition coefficients. These studies were prompted ...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi001038r
更新日期：2000-10-03 00:00:00
abstract：:The slowly hydrolyzed ATP analog adenosine 5'-(gamma-thiotriphosphate) (ATP gamma S) has been used in many studies of the muscle motor protein myosin in order to form a stable "weak binding" state analogous to the actin-S1-ATP complex However, the results from studies using ATP gamma S do not always agree with the res...
journal_title：Biochemistry
pub_type： 杂志文章
doi：10.1021/bi00049a018
更新日期：1995-12-12 00:00:00
