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1.
Sci Transl Med ; 11(502)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31341059

RESUMO

TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common autoimmune diseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of autoimmunity. BMS-986165 is a potent oral agent that similarly blocks receptor-stimulated activation of TYK2 allosterically and with high selectivity and potency afforded through optimized binding to a regulatory domain of the protein. Signaling and functional responses in human TH17, TH1, B cells, and myeloid cells integral to autoimmunity were blocked by BMS-986165, both in vitro and in vivo in a phase 1 clinical trial. BMS-986165 demonstrated robust efficacy, consistent with blockade of multiple autoimmune pathways, in murine models of lupus nephritis and inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases.

2.
J Med Chem ; 62(20): 8953-8972, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31314518

RESUMO

As a member of the Janus (JAK) family of nonreceptor tyrosine kinases, TYK2 plays an important role in mediating the signaling of pro-inflammatory cytokines including IL-12, IL-23, and type 1 interferons. The nicotinamide 4, identified by a SPA-based high-throughput screen targeting the TYK2 pseudokinase domain, potently inhibits IL-23 and IFNα signaling in cellular assays. The described work details the optimization of this poorly selective hit (4) to potent and selective molecules such as 47 and 48. The discoveries described herein were critical to the eventual identification of the clinical TYK2 JH2 inhibitor (see following report in this issue). Compound 48 provided robust inhibition in a mouse IL-12-induced IFNγ pharmacodynamic model as well as efficacy in an IL-23 and IL-12-dependent mouse colitis model. These results demonstrate the ability of TYK2 JH2 domain binders to provide a highly selective alternative to conventional TYK2 orthosteric inhibitors.

3.
J Med Chem ; 62(20): 8973-8995, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31318208

RESUMO

Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.

4.
J Med Chem ; 62(7): 3228-3250, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30893553

RESUMO

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.

5.
Bioorg Med Chem Lett ; 28(18): 3080-3084, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30097367

RESUMO

Incorporation of a suitably-placed electrophilic group transformed a series of reversible BTK inhibitors based on carbazole-1-carboxamide and tetrahydrocarbazole-1-carboxamide into potent, irreversible inhibitors. Removal of one ring from the core of these compounds provided a potent irreversible series of 2,3-dimethylindole-7-carboxamides having excellent potency and improved selectivity, with the additional advantages of reduced lipophilicity and molecular weight.

7.
Anal Biochem ; 497: 8-17, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26743718

RESUMO

XIAP (X-chromosome-linked inhibitor of apoptosis protein) is a central apoptosis regulator that blocks cell death by inhibiting caspase-3, caspase-7, and caspase-9 via binding interactions with the XIAP BIR2 and BIR3 domains (where BIR is baculovirus IAP repeat). Smac protein, in its dimeric form, effectively antagonizes XIAP by concurrently targeting both its BIR2 and BIR3 domains. Here we describe the development of highly sensitive homogeneous time-resolved fluorescence resonance energy transfer (HTRF) assays to measure binding affinities of potent bivalent peptidomimetic inhibitors of XIAP. Our results indicate that these assays can differentiate Smac-mimetic inhibitors with a wide range of binding affinities down to the picomolar range. Furthermore, we demonstrate the utility of these fluorescent tools for characterization of inhibitor off-rates, which as a crucial determinant of target engagement and cellular potency is another important parameter to guide optimization in a structure-based drug discovery effort. Our study also explores how increased inhibitor valency can lead to enhanced potency at multimeric proteins such as IAP.


Assuntos
Transferência Ressonante de Energia de Fluorescência/métodos , Peptidomiméticos/farmacologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Animais , Caspase 3/metabolismo , Linhagem Celular , Humanos , Camundongos Endogâmicos BALB C , Peptidomiméticos/química , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/química
8.
Bioanalysis ; 8(4): 265-74, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26807991

RESUMO

BACKGROUND: A target protein-based affinity extraction LC-MS/MS method was developed to enable plasma level determination following ultralow dosing (0.1-3 µg/kg) of an inhibitor of apoptosis proteins molecule. Methodology & results: Affinity extraction (AE) utilizing immobilized target protein BIR2/BIR3 was used to selectively capture the inhibitor of apoptosis proteins molecule from dog plasma and enable removal of background matrix components. Pretreatment of plasma samples using protein precipitation was found to provide an additional sensitivity gain. A LLOQ of 7.8 pM was achieved by combining protein precipitation with AE. The method was used to support an ultralow dose dog toxicity study. CONCLUSION: AE-LC-MS/MS, utilizing target protein, is a highly sensitive methodology for small molecule quantification with potential for broader applicability.


Assuntos
Análise Química do Sangue/métodos , Fracionamento Químico/métodos , Cromatografia Líquida/métodos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Isoquinolinas/análise , Limite de Detecção , Oligopeptídeos/análise , Bibliotecas de Moléculas Pequenas/análise , Espectrometria de Massas em Tandem/métodos , Animais , Cães , Feminino , Humanos , Proteínas Imobilizadas/antagonistas & inibidores , Proteínas Imobilizadas/química , Proteínas Inibidoras de Apoptose/química , Isoquinolinas/química , Isoquinolinas/farmacologia , Masculino , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
9.
Exp Cell Res ; 338(2): 251-60, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26302264

RESUMO

Cellular levels of inhibitor of apoptosis (IAP) proteins are elevated in multiple human cancers and their activities often play a part in promoting cancer cell survival by blocking apoptotic pathways, controlling signal transduction pathways and contributing to resistance. These proteins function through interactions of their BIR (baculoviral IAP repeat) protein domains with pathway components and these interactions are endogenously antagonized by Smac/Diablo (second mitochondrial activator of caspases/direct IAP binding protein with low isoelectric point). This report describes development of synthetic smac mimetics (SM) and compares their binding, antiproliferative and anti-tumor activities. All dimeric antagonists inhibit in vitro smac tetrapeptide binding to recombinant IAP proteins, rescue IAP-bound caspase-3 activity and show anti-proliferative activity against human A875 melanoma cells. One heterodimeric SM, SM3, binds tightly to IAP proteins in vitro and slowly dissociates (greater than two hours) from these protein complexes compared to the other antagonists. In addition, in vitro SM anti-proliferation potency is influenced by ABCB1 transporter (ATP-binding cassette, sub-family B; MDR1, P-gp) activities and one antagonist, SM5, does not appear to be an ABCB1 efflux pump substrate. All dimeric smac mimetics inhibit the growth of human melanoma A875 tumors implanted in athymic mice at well-tolerated doses. One antagonist, SM4, shows broad spectrum in vivo anti-tumor activity and modulates known pharmacodynamic markers of IAP antagonism. These data taken together demonstrate the range of diverse dimeric IAP antagonist activities and supports their potential as anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Caspase 3/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Mitocondriais/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Biomimética/métodos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Células HCT116 , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína/efeitos dos fármacos
10.
ACS Med Chem Lett ; 6(7): 770-5, 2015 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-26191364

RESUMO

A series of dimeric macrocyclic compounds were prepared and evaluated as antagonists for inhibitor of apoptosis proteins. The most potent analogue 11, which binds to XIAP and c-IAP proteins with high affinity and induces caspase-3 activation and ultimately cell apoptosis, inhibits growth of human melanoma and colorectal cell lines at low nanomolar concentrations. Furthermore, compound 11 demonstrated significant antitumor activity in the A875 human melanoma xenograft model at doses as low as 2 mg/kg on a q3d schedule.

11.
J Med Chem ; 58(3): 1556-62, 2015 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-25584393

RESUMO

The prominent role of IAPs in controlling cell death and their overexpression in a variety of cancers has prompted the development of IAP antagonists as potential antitumor therapies. We describe the identification of a series of heterodimeric antagonists with highly potent antiproliferative activities in cIAP- and XIAP-dependent cell lines. Compounds 15 and 17 further demonstrate curative efficacy in human melanoma and lung cancer xenograft models and are promising candidates for advanced studies.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Neoplasias Experimentais/tratamento farmacológico , Prolina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/patologia , Prolina/síntese química , Prolina/química , Relação Estrutura-Atividade
12.
Bioorg Med Chem Lett ; 24(21): 5022-9, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25278234

RESUMO

Bivalent heterodimeric IAP antagonists that incorporate (R)-tetrahydroisoquinoline in the P3' subunit show high affinity for the BIR2 domain and demonstrated potent IAP inhibitory activities in biochemical and cellular assays. Potent in vivo efficacy was observed in a variety of human tumor xenograft models. The bivalent heterodimeric molecule 3 with a P3-P3' benzamide linker induced pharmacodynamic markers of apoptosis and was efficacious when administered intravenously at a dose of 1mg/kg to mice harboring A875 human melanoma tumors. Analog 5, with a polyamine group incorporated at the P2' thiovaline side chain exhibited antiproliferative activity against the P-gp expressing HCT116/VM46 cell line.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Melanoma/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Tetra-Hidroisoquinolinas/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Neurosci ; 31(30): 10749-51, 2011 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-21795526
14.
Macromol Biosci ; 10(7): 736-45, 2010 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-20480511

RESUMO

Sedimentation velocity (SV) analytical ultracentrifugation has re-emerged as an important tool in the characterization of biological macromolecules and nanoparticles. The computational analysis of the evolution of the macromolecular concentration profile allows the characterization of many hydrodynamic and thermodynamic properties of the macromolecules and their interactions. The Rayleigh interference optical system is often the detection method of choice, for its usually superior data quality and the wide applicability of refractive index sensitive detection. However, the interference optical system is also sensitive to the redistribution of co-solvent molecules, which are not of primary experimental interest. In principle, their contribution can be eliminated by an exact geometric and compositional match of the sample solution and the reference solution, achieving the complete optical subtraction of unwanted buffer signals. Unfortunately, in practice, this can often not be perfectly achieved for various reasons, leading to signal offsets arising from unmatched sedimentation of solvent components. If unrecognized, this can lead to significant misfit, accompanied by significant errors in the macromolecular sedimentation parameters. In the present work, we describe an approach of computationally accounting for signals from sedimenting buffer components through explicitly modeling their redistribution with Lamm equation solutions, implemented in the software SEDFIT. We demonstrate how this can restore the SV analysis to yield a high quality fit of the data and to provide correct macromolecular sedimentation parameters.


Assuntos
Fracionamento Químico/métodos , Interferometria/métodos , Solventes/química , Ultracentrifugação/métodos , Animais , Tampões (Química) , Bovinos , Modelos Químicos , Soroalbumina Bovina/análise , Cloreto de Sódio/análise
15.
Proc Natl Acad Sci U S A ; 106(30): 12329-34, 2009 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-19617541

RESUMO

The activity of many ligand-gated ion channels and cell surface receptors is modulated by small molecules and ions, but an understanding of the underlying molecular mechanisms is scarce. For kainate, but not AMPA subtype glutamate receptors, the binding of Na(+) and Cl(-) ions to discrete, electrostatically coupled sites in the extracellular ligand binding domain (LBD) dimer assembly regulates the rate of entry into the desensitized state, which occurs when the dimer interface ruptures and the channel closes. Studies on glutamate receptors have defined the LBD dimer assembly as a key functional unit that controls activation and desensitization. Here we use analytical ultracentrifugation to probe the energetic effects of allosteric ions on kainate receptor dimer stability in solution, using a GluR6 mutant that desensitizes slowly. Our results show that sodium and chloride ions modulate kainate receptor dimer affinity as much as 50-fold, and that removal of either Cl(-) or Na(+) disrupts the dimer. The applicability of a similar allosteric mechanism for modulation of delta2 glutamate receptors by Ca(2+) was also tested. Our results indicate that ions can contribute substantial free energy to active state stabilization in both these receptors, and provide quantitative measurements of the energetic consequences of allosteric ion binding to a ligand-gated ion channel.


Assuntos
Cloretos/química , Estrutura Terciária de Proteína , Receptores de Ácido Caínico/química , Sódio/química , Regulação Alostérica , Sequência de Aminoácidos , Sítios de Ligação/genética , Cálcio/química , Cálcio/metabolismo , Linhagem Celular , Cloretos/metabolismo , Transferência de Energia , Cinética , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Multimerização Proteica , Receptores de Ácido Caínico/genética , Receptores de Ácido Caínico/metabolismo , Sódio/metabolismo , Ultracentrifugação
16.
EMBO J ; 28(10): 1518-30, 2009 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-19339989

RESUMO

AMPA and kainate receptors mediate fast synaptic transmission. AMPA receptor ligand-binding domains form dimers, which are key functional units controlling ion-channel activation and desensitization. Dimer stability is inversely related to the rate and extent of desensitization. Kainate and AMPA receptors share common structural elements, but functional measurements suggest that subunit assembly and gating differs between these subtypes. To investigate this, we constructed a library of GluR6 kainate receptor mutants and directly measured changes in kainate receptor dimer stability by analytical ultracentrifugation, which, combined with electrophysiological experiments, revealed an inverse correlation between dimer stability and the rate of desensitization. We solved crystal structures for a series of five GluR6 mutants, to understand the molecular mechanisms for dimer stabilization. We demonstrate that the desensitized state of kainate receptors acts as a deep energy well offsetting the stabilizing effects of dimer interface mutants, and that the deactivation of kainate receptor responses is dominated by entry into desensitized states. Our results show how neurotransmitter receptors with similar structures and gating mechanisms can exhibit strikingly different functional properties.


Assuntos
Multimerização Proteica , Receptores de Ácido Caínico/química , Receptores de Ácido Caínico/metabolismo , Sequência de Aminoácidos , Cristalografia por Raios X , Modelos Biológicos , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Quaternária de Proteína , Receptores de Ácido Caínico/genética , Homologia de Sequência de Aminoácidos
17.
Proc Natl Acad Sci U S A ; 101(42): 15005-12, 2004 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-15479763

RESUMO

A conundrum has arisen in the study of the structural states of the GroEL-GroES chaperonin machine: When either ATP or ADP is added along with GroES to GroEL, the same asymmetric complex, with one ring in a GroES-domed state, is observed by either x-ray crystallographic study or cryoelectron microscopy. Yet only ATP/GroES can trigger productive folding inside the GroES-encapsulated cis cavity by ejecting bound polypeptide from hydrophobic apical binding sites during attendant rigid body elevation and twisting of these domains. Here, we show that this difference occurs because polypeptide substrate in fact presents a load on the apical domains, and, although ATP can counter this load effectively, ADP cannot. We monitored apical domain movement in real time by fluorescence resonance energy transfer (FRET) between a fixed equatorial fluorophore and one attached to the mobile apical domain. In the absence of bound polypeptide, addition of either ATP/GroES or ADP/GroES to GroEL produced the same rapid rate and extent of decrease of FRET (t(1/2) < 1 sec), reflecting similarly rapid apical movement to the same end-state and explaining the results of the structural studies, which were all carried out in the absence of substrate polypeptide. But in the presence of bound malate dehydrogenase or rhodanese, whereas similar rapid and extensive FRET changes were observed with ATP/GroES, the rate of FRET change with ADP/GroES was slowed by >100-fold and the extent of change was reduced, indicating that the apical domains opened in a slow and partial fashion. These results indicate that the free energy of gamma-phosphate binding, measured earlier as 43 kcal per mol (1 cal = 4.184 J) of rings, is required for driving the forceful excursion or "power stroke" of the apical domains needed to trigger release of the polypeptide load into the central cavity.


Assuntos
Chaperonina 60/química , Chaperonina 60/metabolismo , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , Chaperonina 10/química , Chaperonina 10/genética , Chaperonina 10/metabolismo , Chaperonina 60/genética , Transferência Ressonante de Energia de Fluorescência , Corantes Fluorescentes , Cinética , Substâncias Macromoleculares , Modelos Moleculares , Dobramento de Proteína , Estrutura Terciária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
18.
J Mol Biol ; 342(1): 229-45, 2004 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-15313620

RESUMO

Large rigid-body domain movements are critical to GroEL-mediated protein folding, especially apical domain elevation and twist associated with the formation of a folding chamber upon binding ATP and co-chaperonin GroES. Here, we have modeled the anisotropic displacements of GroEL domains from various crystallized states, unliganded GroEL, ATPgammaS-bound, ADP-AlFx/GroES-bound, and ADP/GroES bound, using translation-libration-screw (TLS) analysis. Remarkably, the TLS results show that the inherent motions of unliganded GroEL, a polypeptide-accepting state, are biased along the transition pathway that leads to the folding-active state. In the ADP-AlFx/GroES-bound folding-active state the dynamic modes of the apical domains become reoriented and coupled to the motions of bound GroES. The ADP/GroES complex exhibits these same motions, but they are increased in magnitude, potentially reflecting the decreased stability of the complex after nucleotide hydrolysis. Our results have allowed the visualization of the anisotropic molecular motions that link the static conformations previously observed by X-ray crystallography. Application of the same analyses to other macromolecules where rigid body motions occur may give insight into the large scale dynamics critical for function and thus has the potential to extend our fundamental understanding of molecular machines.


Assuntos
Trifosfato de Adenosina/análogos & derivados , Chaperonina 60/química , Proteínas de Escherichia coli/química , Dobramento de Proteína , Estrutura Terciária de Proteína , Difosfato de Adenosina/química , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Chaperonina 10/metabolismo , Chaperonina 60/metabolismo , Cristalografia por Raios X , Proteínas de Escherichia coli/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Ligação Proteica
19.
EMBO J ; 22(19): 4877-87, 2003 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-14517228

RESUMO

Productive cis folding by the chaperonin GroEL is triggered by the binding of ATP but not ADP, along with cochaperonin GroES, to the same ring as non-native polypeptide, ejecting polypeptide into an encapsulated hydrophilic chamber. We examined the specific contribution of the gamma-phosphate of ATP to this activation process using complexes of ADP and aluminium or beryllium fluoride. These ATP analogues supported productive cis folding of the substrate protein, rhodanese, even when added to already-formed, folding-inactive cis ADP ternary complexes, essentially introducing the gamma-phosphate of ATP in an independent step. Aluminium fluoride was observed to stabilize the association of GroES with GroEL, with a substantial release of free energy (-46 kcal/mol). To understand the basis of such activation and stabilization, a crystal structure of GroEL-GroES-ADP.AlF3 was determined at 2.8 A. A trigonal AlF3 metal complex was observed in the gamma-phosphate position of the nucleotide pocket of the cis ring. Surprisingly, when this structure was compared with that of the previously determined GroEL-GroES-ADP complex, no other differences were observed. We discuss the likely basis of the ability of gamma-phosphate binding to convert preformed GroEL-GroES-ADP-polypeptide complexes into the folding-active state.


Assuntos
Trifosfato de Adenosina/metabolismo , Chaperonina 10/metabolismo , Chaperonina 60/metabolismo , Dobramento de Proteína , Organofosfatos/metabolismo , Tiossulfato Sulfurtransferase/metabolismo
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