RESUMO
Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1-5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance6. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment-which contributes to virologic failure, resistance generation and viral transmission-as well as of pre-exposure prophylaxis, leading to new infections1,2,4,7-9. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence10. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log10-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV.
Assuntos
Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Proteínas do Capsídeo/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Adolescente , Adulto , Fármacos Anti-HIV/química , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Linhagem Celular , Células Cultivadas , Farmacorresistência Viral/genética , Feminino , HIV-1/crescimento & desenvolvimento , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Replicação Viral/efeitos dos fármacos , Adulto JovemRESUMO
We hereby disclose the discovery of inhibitors of CaMKII (7h and 7i) that are highly potent in rat ventricular myocytes, selective against hERG and other off-target kinases, while possessing good CaMKII tissue isoform selectivity (cardiac γ/δ vs. neuronal α/ß). In vitro and in vivo ADME/PK studies demonstrated the suitability of these CaMKII inhibitors for PO (7h rat Fâ¯=â¯73%) and IV pharmacological studies.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
Idelalisib (also known as GS-1101, CAL-101, IC489666, and Zydelig) is a PI3Kδ inhibitor that has recently been approved for the treatment of several hematological malignancies. Given its use in human diseases, we needed a clear picture of how idelalisib binds to and inhibits PI3Kδ. Our data show that idelalisib is a potent and selective inhibitor of the kinase activity of PI3Kδ. A kinetic characterization clearly demonstrated ATP-competitive inhibition, and several additional biochemical and biophysical assays showed that the compound binds reversibly and noncovalently to the kinase. A crystal structure of idelalisib bound to the p110δ subunit of PI3Kδ furthers our understanding of the binding interactions that confer the potency and selectivity of idelalisib.
Assuntos
Fosfatidilinositol 3-Quinases/química , Purinas/química , Quinazolinonas/química , Trifosfato de Adenosina/química , Androstadienos/química , Animais , Ligação Competitiva , Domínio Catalítico , Classe I de Fosfatidilinositol 3-Quinases , Classe Ia de Fosfatidilinositol 3-Quinase/química , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Cinética , Camundongos , Modelos Moleculares , Inibidores de Fosfoinositídeo-3 Quinase , Ligação Proteica , WortmaninaRESUMO
HIV capsid protein is an important target for antiviral drug design. High-throughput screening campaigns have identified two classes of compounds (PF74 and BI64) that directly target HIV capsid, resulting in antiviral activity against HIV-1 and HIV-2 laboratory strains. Using recombinant proteins, we developed a suite of label-free assays to mechanistically understand how these compounds modulate capsid activity. PF74 preferentially binds to the preassembled hexameric capsid form and prevents disruption of higher-order capsid structures by stabilizing capsid intersubunit interactions. BI64 binds only the monomeric capsid and locks the protein in the assembly incompetent monomeric form by disrupting capsid intersubunit interactions. We also used these assays to characterize the interaction between capsid and the host protein cleavage and polyadenylation specific factor 6 (CPSF6). Consistent with recently published results, our assays revealed CPSF6 activates capsid polymerization and preferentially binds to the preassembled hexameric capsid form similar to the small molecule compound, PF74. Furthermore, these label-free assays provide a robust method for facilitating the identification of a different class of small molecule modulators of capsid function.
Assuntos
Fármacos Anti-HIV/farmacologia , Técnicas Biossensoriais/métodos , Capsídeo/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Sequência de Aminoácidos , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Benzimidazóis/farmacologia , Capsídeo/química , HIV-1 , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Dados de Sequência Molecular , Fenilalanina/análogos & derivados , Fenilalanina/química , Fenilalanina/metabolismo , Fenilalanina/farmacologia , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Poliadenilação e Clivagem de mRNA/genéticaRESUMO
The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford increased activity against the target enzyme and in the cell-based replicon assay system.
Assuntos
Antivirais/farmacologia , Química Farmacêutica/métodos , Hepacivirus/enzimologia , Quinolonas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Sítio Alostérico , Antivirais/síntese química , Sítios de Ligação , Cristalografia por Raios X/métodos , Desenho de Fármacos , Ligação de Hidrogênio , Hidrólise , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Quinolonas/síntese química , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/química , Raios XRESUMO
Hepatitis C virus (HCV) infection is treated with a combination of peginterferon alfa-2a/b and ribavirin. To address the limitations of this therapy, numerous small molecule agents are in development, which act by directly affecting key steps in the viral life-cycle. Herein we describe our discovery of quinolone derivatives, novel small-molecules that inhibit NS5b polymerase, a key enzyme of the viral life-cycle. A crystal structure of a quinoline analog bound to NS5B reveals that this class of compounds binds to allosteric site-II (non-nucleoside inhibitor-site 2, NNI-2) of this protein.
Assuntos
Antivirais/química , Inibidores Enzimáticos/química , Hepacivirus/enzimologia , Quinolonas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Antivirais/síntese química , Antivirais/farmacologia , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Quinolonas/síntese química , Quinolonas/farmacologia , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
Atropisomerism is a type of axial chirality in which enantiomers or diastereoisomers arise due to hindered rotation around a bond axis. In this manuscript, we report a case in which torsional scan studies guided the thoughtful creation of a restricted axis of rotation between two heteroaromatic systems of a phosphoinositide 3-kinase (PI3K) ß inhibitor, generating a pair of atropisomeric compounds with significantly different pharmacological and pharmacokinetic profiles. Emblematic of these differences, the metabolism of inactive ( M)-28 is primarily due to the cytosolic enzyme aldehyde oxidase, while active ( P)-28 has lower affinity for aldehyde oxidase, resulting in substantially better metabolic stability. Additionally, we report torsional scan and experimental studies used to determine the barriers of rotation of this novel PI3Kß inhibitor.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Trifosfato de Adenosina/metabolismo , Animais , Inibidores Enzimáticos/metabolismo , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Conformação Proteica , Quinazolinas/química , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Estereoisomerismo , Especificidade por SubstratoRESUMO
A new series of nonpeptidic cathepsin K inhibitors that are based on a beta-substituted cyclohexanecarboxamide motif has been developed. Lead optimization yielded compounds with sub-nanomolar potency and exceptional selectivity profiles against cathepsins B, L, and S. Use of fluorine atoms to block metabolism on the cyclohexyl ring led to compounds with excellent pharmacokinetic properties. Considering the well-established role of cathepsin K in osteoclast-mediated bone turnover, compounds such as (-)-34a (hrab Cat K IC(50) 0.28 nM; >800-fold selectivity vs Cat B, L, and S; PK data in dogs: F 55%, t(1/2) = 15 h) exhibit great potential for development as an orally bioavailable therapeutic for treatment of diseases that involve bone loss.
Assuntos
Amidas/síntese química , Aminoacetonitrila/análogos & derivados , Catepsinas/antagonistas & inibidores , Cicloexanos/síntese química , Amidas/química , Amidas/farmacologia , Aminoacetonitrila/síntese química , Aminoacetonitrila/química , Aminoacetonitrila/farmacologia , Animais , Disponibilidade Biológica , Catepsina K , Catepsinas/química , Cristalografia por Raios X , Cicloexanos/química , Cicloexanos/farmacologia , Cães , Meia-Vida , Masculino , Modelos Moleculares , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Hepsin is an integral membrane protein that may participate in cell growth and in maintaining proper cell morphology and is overexpressed in a number of primary tumors. We have determined the 1.75 A resolution structure of the extracellular component of human hepsin. This structure includes a 255-residue trypsin-like serine protease domain and a 109-residue region that forms a novel, poorly conserved, scavenger receptor cysteine-rich (SRCR) domain. The two domains are associated with each other through a single disulfide bond and an extensive network of noncovalent interactions. The structure suggests how the extracellular region of hepsin may be positioned with respect to the plasma membrane.
Assuntos
Espaço Extracelular/química , Receptores Imunológicos/química , Serina Endopeptidases/química , Sequência de Aminoácidos , Membrana Celular/química , Humanos , Dados de Sequência Molecular , Conformação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptores Depuradores , Alinhamento de SequênciaRESUMO
Modulation of the acetylation state of histones plays a pivotal role in the regulation of gene expression. Histone deacetylases (HDACs) catalyze the removal of acetyl groups from lysines near the N termini of histones. This reaction promotes the condensation of chromatin, leading to repression of transcription. HDAC deregulation has been linked to several types of cancer, suggesting a potential use for HDAC inhibitors in oncology. Here we describe the first crystal structures of a human HDAC: the structures of human HDAC8 complexed with four structurally diverse hydroxamate inhibitors. This work sheds light on the catalytic mechanism of the HDACs, and on differences in substrate specificity across the HDAC family. The structure also suggests how phosphorylation of Ser39 affects HDAC8 activity.
Assuntos
Histona Desacetilases/química , Proteínas Repressoras/química , Sequência de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X , Histona Desacetilases/metabolismo , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Molecular , Conformação Proteica , Proteínas Repressoras/metabolismo , Especificidade por SubstratoRESUMO
Aberrant signaling of phosphoinositide 3-kinase δ (PI3Kδ) has been implicated in numerous pathologies including hematological malignancies and rheumatoid arthritis. Described in this manuscript are the discovery, optimization, and in vivo evaluation of a novel series of pyridine-containing PI3Kδ inhibitors. This work led to the discovery of 35, a highly selective inhibitor of PI3Kδ which displays an excellent pharmacokinetic profile and is efficacious in a rodent model of rheumatoid arthritis.
RESUMO
Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) is an appealing target for several hematological malignancies and inflammatory diseases. Herein, we describe the discovery and optimization of a series of propeller shaped PI3Kδ inhibitors comprising a novel triaminopyrimidine hinge binder. Combinations of electronic and structural strategies were employed to mitigate aldehyde oxidase mediated metabolism. This medicinal chemistry effort culminated in the identification of 52, a potent and highly selective inhibitor of PI3Kδ that demonstrates efficacy in a rat model of arthritis.
Assuntos
Artrite Experimental/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Quinazolinonas/farmacologia , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/enzimologia , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/enzimologia , Células Cultivadas , Colágeno/toxicidade , Cristalografia por Raios X , Modelos Animais de Doenças , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Quinazolinonas/química , Quinazolinonas/farmacocinética , Ratos , Ratos Endogâmicos Lew , Distribuição TecidualRESUMO
Cathepsin F is a lysosomal cysteine protease of the papain family, and likely plays a regulatory role in processing the invariant chain that is associated with the major histocompatibility complex (MHC) class II. Evidence suggests that inhibiting cathepsin F activity will block MHC class II processing in macrophages. Consequently, inhibitors of this enzyme may be useful in treating certain diseases that involve an inappropriate or excessive immune response. We have determined the 1.7A structure of the mature domain of human cathepsin F associated with an irreversible vinyl sulfone inhibitor. This structure provides a basis for understanding cathepsin F's substrate specificity, and suggests ways of identifying potent and selective inhibitors of this enzyme.
Assuntos
Adjuvantes Imunológicos/química , Catepsinas/química , Sequência de Aminoácidos , Sítios de Ligação , Encéfalo/fisiologia , Catepsina F , Catepsinas/genética , Catepsinas/isolamento & purificação , Catepsinas/metabolismo , Cristalização , Cristalografia por Raios X , Cisteína Endopeptidases , Antígenos de Histocompatibilidade Classe II/química , Humanos , Dados de Sequência Molecular , Estrutura Molecular , Papaína/metabolismo , Inibidores de Proteases/química , Conformação Proteica , Dobramento de Proteína , Homologia de Sequência de Aminoácidos , Especificidade por SubstratoRESUMO
A site-directed mutant of the serine protease urokinase-type plasminogen activator (uPA), was produced to assess the contribution of the Ser190 side-chain to the affinity and selectivity of lead uPA inhibitors in the absence of other differences present in comparisons of natural proteases. Crystallography and enzymology involving WT and Ala190 uPA were used to calculate free energy binding contributions of hydrogen bonds involving the Ser190 hydroxyl group (O(gamma)(Ser190)) responsible for the remarkable selectivity of 6-halo-5-amidinoindole and 6-halo-5-amidinobenzimidazole inhibitors toward uPA and against natural Ala190 protease anti-targets. Crystal structures of uPA complexes of novel, active site-directed arylguanidine and 2-aminobenzimidazole inhibitors of WT uPA, together with associated K(i) values for WT and Ala190 uPA, also indicate a significant role of Ser190 in the binding of these classes of uPA inhibitors. Structures and associated K(i) values for a lead inhibitor (CA-11) bound to uPA and to five other proteases, as well as for other leads bound to multiple proteases, help reveal the features responsible for the potency (K(i)=11nM) and selectivity of the remarkably small inhibitor, CA-11. The 6-fluoro-5-amidinobenzimidzole, CA-11, is more than 1000-fold selective against natural Ala190 protease anti-targets, and more than 100-fold selective against other Ser190 anti-targets.
Assuntos
Alanina/química , Amidinas/química , Indóis/química , Inibidores de Proteases/síntese química , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Alanina/metabolismo , Benzimidazóis/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Guanidina/farmacologia , Humanos , Ligação de Hidrogênio , Estrutura Molecular , Mutagênese Sítio-Dirigida , Mutação , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Ligação Proteica , Serina/química , Serina/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato , Termodinâmica , Ativador de Plasminogênio Tipo Uroquinase/química , Ativador de Plasminogênio Tipo Uroquinase/genética , Água/químicaRESUMO
We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.
Assuntos
Benzamidas/síntese química , Conservadores da Densidade Óssea/síntese química , Catepsinas/antagonistas & inibidores , Nitrilas/síntese química , Tiazóis/síntese química , Administração Oral , Animais , Benzamidas/química , Benzamidas/farmacologia , Disponibilidade Biológica , Biomarcadores/urina , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/farmacologia , Reabsorção Óssea/urina , Catepsina K , Catepsinas/química , Bovinos , Colágeno/antagonistas & inibidores , Colágeno/metabolismo , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Cinética , Macaca mulatta , Modelos Moleculares , Estrutura Molecular , Nitrilas/química , Nitrilas/farmacologia , Coelhos , Ratos , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologiaRESUMO
The structural mechanism by which nonstructural protein 3 (NS3) from the hepatitis C virus (HCV) translocates along RNA is currently unknown. HCV NS3 is an ATP-dependent motor protein essential for viral replication and a member of the superfamily 2 helicases. Crystallographic analysis using a labeled RNA oligonucleotide allowed us to unambiguously track the positional changes of RNA bound to full-length HCV NS3 during two discrete steps of the ATP hydrolytic cycle. The crystal structures of HCV NS3, NS3 bound to bromine-labeled RNA, and a tertiary complex of NS3 bound to labeled RNA and a non-hydrolyzable ATP analog provide a direct view of how large domain movements resulting from ATP binding and hydrolysis allow the enzyme to translocate along the phosphodiester backbone. While directional translocation of HCV NS3 by a single base pair per ATP hydrolyzed is observed, the 3' end of the RNA does not shift register with respect to a conserved tryptophan residue, supporting a "spring-loading" mechanism that leads to larger steps by the enzyme as it moves along a nucleic acid substrate.
Assuntos
Hepacivirus/enzimologia , RNA Helicases/química , Transporte de RNA , Proteínas não Estruturais Virais/química , Adenosina Trifosfatases/química , Trifosfato de Adenosina/química , Cristalografia , Humanos , Estrutura Terciária de Proteína , Especificidade por SubstratoRESUMO
Falcipain-2 (FP2), the major cysteine protease of the human malaria parasite Plasmodium falciparum, is a hemoglobinase and promising drug target. Here we report the crystal structure of FP2 in complex with a protease inhibitor, cystatin. The FP2 structure reveals two previously undescribed cysteine protease structural motifs, designated FP2(nose) and FP2(arm), in addition to details of the active site that will help focus inhibitor design. Unlike most cysteine proteases, FP2 does not require a prodomain but only the short FP2(nose) motif to correctly fold and gain catalytic activity. Our structure and mutagenesis data suggest a molecular basis for this unique mechanism by highlighting the functional role of two Tyr within FP2(nose) and a conserved Glu outside this motif. The FP2(arm) motif is required for hemoglobinase activity. The structure reveals topographic features and a negative charge cluster surrounding FP2(arm) that suggest it may serve as an exo-site for hemoglobin binding. Motifs similar to FP2(nose) and FP2(arm) are found only in related plasmodial proteases, suggesting that they confer malaria-specific functions.
Assuntos
Cisteína Endopeptidases/química , Hemoglobinas/metabolismo , Plasmodium falciparum/enzimologia , Dobramento de Proteína , Estrutura Terciária de Proteína , Sequência de Aminoácidos , Animais , Cristalografia por Raios X , Cistatinas/química , Cistatinas/metabolismo , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Ligação Proteica , Alinhamento de Sequência , Homologia de Sequência de AminoácidosRESUMO
A series of novel alpha-keto-[1,2,4]-oxadiazoles has been synthesized as human tryptase inhibitors for evaluation as a new class of anti-asthmatic agent. The inhibitor design is focused on using a prime-side hydrophobic pocket and the S2 pocket of beta-tryptase to achieve inhibition potency and selectivity over other serine proteases.
Assuntos
Oxazóis/farmacologia , Serina Endopeptidases/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Cinética , Oxazóis/química , TriptasesRESUMO
Improved peptide-based inhibitors of human beta tryptase were discovered using information gleaned from tripeptide library screening and structure-guided design methods, including fragment screening. Our efforts sought to improve this class of inhibitors by replacing the traditional Lys or Arg P1 element. The optimized compounds display low nanomolar potency against the mast cell target and several hundred-fold selectivity with respect to serine protease off targets. Thus, replacement of Lys/Arg at P1 in a peptide-like scaffold does not need to be accompanied by a loss in target affinity.
Assuntos
Serina Endopeptidases/efeitos dos fármacos , Inibidores de Serina Proteinase/química , Cristalografia por Raios X , Modelos Moleculares , Conformação Proteica , Inibidores de Serina Proteinase/farmacologia , TriptasesRESUMO
Cathepsin F is a cysteine protease believed to be involved in the antigen-presenting process of the class II major histocompatibility complex (MHC-II) in macrophages. It has been expressed, purified and crystallized. A complete data set to a resolution of 2.5 A has been collected at room temperature. The Laue group was determined to be orthorhombic, space group P2(1)2(1)2, with unit-cell parameters a = 68.9, b = 104.8, c = 68.5 A.