共查询到20条相似文献,搜索用时 15 毫秒
1.
Regulated activation of receptor tyrosine kinases depends on both the presence of the receptors at the cell surface and on the availability of their ligands. In Drosophila, the torso tyrosine kinase receptor is distributed along the surface of the embryo but it is only activated at the poles by a diffusible extracellular ligand generated at each pole that is trapped by the receptor, thereby impeding further diffusion. Although it is known that this signal depends on the activity of several genes, such as torso-like and trunk, it is still unclear how is generated. The identification of the signal responsible for the torso receptor activation is an essential step towards understanding the mechanism that regulates the local restriction of torso signalling. Here we report that a fragment containing the carboxy-terminal 108 amino acids of the trunk protein retains trunk activity and is sufficient to activate torso signalling. We also show that this fragment bypasses the requirements for the other genes involved in the activation of the torso receptor. These results suggest that a cleaved form of the trunk protein acts as a signal for the torso receptor. We therefore propose that the restricted activation of the torso receptor is defined by the spatial control of the proteolytic processing of the trunk protein. 相似文献
2.
CR1/CR2 interactions modulate the functions of the cell surface epidermal growth factor receptor 总被引:3,自引:0,他引:3
Walker F Orchard SG Jorissen RN Hall NE Zhang HH Hoyne PA Adams TE Johns TG Ward C Garrett TP Zhu HJ Nerrie M Scott AM Nice EC Burgess AW 《The Journal of biological chemistry》2004,279(21):22387-22398
Recent crystallographic data on the isolated extracellular domain of the epidermal growth factor receptor (EGFR) have suggested a model for its activation by ligand. We have tested this model in the context of the full-length EGFR displayed at the cell surface, by introducing mutations in two regions (CR1 and CR2) of the extracellular domain thought to be critical for regulation of receptor activation. Mutations in the CR1 and CR2 domains have opposing effects on ligand binding affinity, receptor dimerization, tyrosine kinase activation, and signaling competence. Tyr(246) is a critical residue in the CR1 loop, which is implicated in the positioning and stabilization of the receptor dimer interface after ligand binding; mutations of Tyr(246) impair or abolish receptor function. Mutations in CR2, which weaken the interaction that restricts the receptor to the tethered (inactive) state, enhance responsiveness to EGF by increasing affinity for the ligand. However, weakening of the CR1/CR2 interaction does not result in spontaneous activation of the receptors' kinase. We have used an antibody (mAb 806), which recognizes a transition state of the EGF receptor between the negatively constrained, tethered state and the fully active back-to-back dimer conformation, to follow conformational changes in the wild-type and mutant EGF receptors after ligand binding. Our results suggest that EGFR on the cell surface can be untethered, but this form is inactive; thus, untethering of the receptor is not sufficient for activation, and ligand binding is essential for the correct positioning of the two receptor subunits to achieve kinase activation. 相似文献
3.
Regulated activation of receptor tyrosine kinases depends both on the presence of the receptors at the cell surface and on the availability of their ligands. In Drosophila the torso (tor) tyrosine kinase receptor is distributed along the surface of the embryo but it is only activated at the poles by a diffusible extracellular ligand generated at each pole which is trapped by the receptor, thereby impeding further diffusion. However, it is not well understood how this signal is generated, although it is known to depend on the activity of many genes such as torso-like (tsl) and trunk (trk). To further investigate the mechanism involved in the local activation of the tor receptor we have altered the normal expression of the tsl protein by generating females in which the tsl gene is expressed in the oocyte under the control of the tor promoter rather than in the ovarian follicle cells. Analysis of the phenotypes generated by this hybrid gene and its interactions with mutations in other genes in the pathway has enabled us to further dissect the mechanism of tor receptor activation and to define more precisely the role of the different genes acting in this process. 相似文献
4.
Degradation of the Met tyrosine kinase receptor by the ubiquitin-proteasome pathway. 总被引:19,自引:2,他引:17
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M Jeffers G A Taylor K M Weidner S Omura G F Vande Woude 《Molecular and cellular biology》1997,17(2):799-808
The Met tyrosine kinase receptor is a widely expressed molecule which mediates pleiotropic cellular responses following activation by its ligand, hepatocyte growth factor/scatter factor (HGF/SF). In this communication we demonstrate that significant Met degradation is induced by HGF/SF and that this degradation can be blocked by lactacystin, an inhibitor of proteasome activity. We also show that Met is rapidly polyubiquitinated in response to ligand and that polyubiquitinated Met molecules, which are normally unstable, are stabilized by lactacystin. Both HGF/SF-induced degradation and polyubiquitination of Met were shown to be dependent on the receptor possessing intact tyrosine kinase activity. Finally, we found that a normally highly labile 55-kDa fragment of the Met receptor is stabilized by lactacystin and demonstrate that it represents a cell-associated remnant that is generated following the ligand-independent proteolytic cleavage of the Met receptor in its extracellular domain. This truncated Met molecule encompasses the kinase domain of the receptor and is itself tyrosine phosphorylated. We conclude that the ubiquitin-proteasome pathway plays a significant role in the degradation of the Met tyrosine kinase receptor as directed by ligand-dependent and -independent signals. We propose that this proteolytic pathway may be important for averting cellular transformation by desensitizing Met signaling following ligand stimulation and by eliminating potentially oncogenic fragments generated via extracellular cleavage of the Met receptor. 相似文献
5.
Biochemical analysis of torso and D-raf during Drosophila embryogenesis: implications for terminal signal transduction. 总被引:5,自引:2,他引:3
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Determination of anterior and posterior terminal structures of Drosophila embryos requires activation of two genes encoding putative protein kinases, torso and D-raf. In this study, we demonstrate that Torso has intrinsic tyrosine kinase activity and show that it is transiently tyrosine phosphorylated (activated) at syncytial blastoderm stages. Torso proteins causing a gain-of-function phenotype are constitutively tyrosine phosphorylated, while Torso proteins causing a loss-of-function phenotype lack tyrosine kinase activity. The D-raf gene product, which is required for Torso function, is identified as a 90-kDa protein with intrinsic serine/threonine kinase activity. D-Raf is expressed throughout embryogenesis; however, the phosphorylation state of the protein changes during development. In wild-type embryos, D-Raf is hyperphosphorylated at 1 to 2 h after egg laying, and thereafter only the most highly phosphorylated form is detected. Embryos lacking Torso activity, however, show significant reductions in D-Raf protein expression rather than major alterations in the protein's phosphorylation state. This report provides the first biochemical analysis of the terminal signal transduction pathway in Drosophila embryos. 相似文献
6.
Aline Bennasroune Marie-Claude Boutterin 《Biochemical and biophysical research communications》2010,398(4):702-706
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase essentially and transiently expressed during development of the central and peripheral nervous system. The nature of the cognate ligand of this receptor in Vertebrates is still a matter of debate. During synaptic transmission the release of ionic zinc found in vesicles of certain glutamatergic and gabaergic terminals may act as a neuromodulator by binding to pre- or post-synaptic receptors. Recently, zinc has been shown to activate the receptor tyrosine kinase, TrkB, independently of neurotrophins. This activation occurs via increasing the Src family kinase activity. In the present study, we investigated whether the ALK activity could be modulated by extracellular zinc. We first showed that zinc alone rapidly activates ALK. This activation is dependent of ALK tyrosine kinase activity and dimerization of the receptor but is independent of Src family kinase activity. In contrast, addition of sodium pyrithione, a zinc ionophore, led to a further activation of ALK. This stronger activation is dependent of Src family kinase but independent of ALK activity and dimerization. In conclusion, zinc could constitute an endogenous ligand of ALK in vertebrates. 相似文献
7.
J Casanova 《Development (Cambridge, England)》1990,110(2):621-628
The specification of the most anterior and posterior domains of the Drosophila embryo depends on the activity of the torso protein, a putative tyrosine kinase receptor. Localized torso activity at the poles of the embryo generates graded information that specifies distinct portions of the body. The primary response to the terminal signal in the posterior end of the embryo is likely to be the activation of the gap genes huckebein and tailless. Here I address the question of how the graded maternal signal generates different elements of the pattern at the posterior end of the embryo and what role huckebein and tailless activities may play in this process. These experiments show that distinctly localized activities of huckebein and tailless are responsible for the appropriate expression of other genes known to be under the control of the terminal system. Moreover, they suggest that different elements of the terminal pattern can be specified in response to distinct levels of graded tailless activity. 相似文献
8.
Profound ligand-independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type II. 总被引:16,自引:2,他引:14
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M K Webster P Y D'Avis S C Robertson D J Donoghue 《Molecular and cellular biology》1996,16(8):4081-4087
Thanatophoric dysplasia type II (TDII) is a neonatal lethal skeletal dysplasia caused by a recurrent Lys-650-->Glu mutation within the highly conserved activation loop of the kinase domain of fibroblast growth factor receptor 3 (FGFR3). We demonstrate here that this mutation results in profound constitutive activation of the FGFR3 tyrosine kinase, approximately 100-fold above that of wild-type FGFR3. The mechanism of FGFR3 activation in TDII was probed by constructing various point mutations in the activation loop. Substitutions at position 650 indicated that not only Glu but also Asp and, to a lesser extent, Gln and Leu result in pronounced constitutive activation of FGFR3. Additional mutagenesis within the beta10-beta11 loop region (amino acids Tyr-647 to Leu-656) demonstrated that amino acid 650 is the only residue which can activate the receptor when changed to a Glu, indicating a specificity of position as well as charge for mutations which can give rise to kinase activation. Furthermore, when predicted sites of autophosphorylation at Tyr-647 and Tyr-648 were mutated to Phe, either singly or in combination, constitutive kinase activity was still observed in response to the Lys-650-->Glu mutation, although the effect of these mutations on downstream signalling was not investigated. Our data suggest that the molecular effect of the TDII activation loop mutation is to mimic the conformational changes that activate the tyrosine kinase domain, which are normally initiated by ligand binding and autophosphorylation. These results have broad implications for understanding the molecular basis of other human developmental syndromes that involve mutations in members of the FGFR family. Moreover, these findings are relevant to the study of kinase regulation and the design of activating mutations in related tyrosine kinases. 相似文献
9.
Oncogenic receptor tyrosine kinase in leukemia. 总被引:2,自引:0,他引:2
M Mizuki S Ueda I Matsumura J Ishiko J Schw?ble H Serve Y Kanakura 《Cellular and molecular biology, including cyto-enzymology》2003,49(6):907-922
Growth, survival and differentiation of hematopoietic cells are regulated by the interaction between hematopoietic growth factors and their receptors. While the defect in this interaction results in an insufficient hematopoiesis, the aberrantly elevated activation leads to the transformation of hematopoietic cells. The constitutive active mutations of receptor tyrosine kinase, such as c-Kit platelet-derived growth factor receptor (PDGFR) or fins-like tyrosine kinase 3 (Flt3), play a major role in the development of hematopoietic neoplasia. The constitutive activation is provoked by several mechanisms, such as making fusion genes by chromosomal translocations, or various mutations involving regulatory regions of the receptor. The chromosomal translocation brings the receptor intracytoplasmic domain juxtaposed to an unrelated molecule which has dimerization or multimerization motif, resulting in the constitutive dimerization of the receptor. The missense, insertion or deletion mutations in the regulatory regions, such as juxtamembrane domain, activation loop and extracellular domain, cause constitutive activation by releasing the respective auto-inhibitory functions of each regulatory region. Constitutive active receptors generate different signals quantitatively and qualitatively from wild type receptor, which mediate the oncogenic phenotype. Given the frequent involvement of constitutive active receptor tyrosine kinase in hematopoietic malignancies, targeted inhibitions of active tyrosine kinase and downstream aberrant signaling are rapidly developing novel therapeutic modality with much promise. 相似文献
10.
TrkA receptor ectodomain cleavage generates a tyrosine-phosphorylated cell-associated fragment 总被引:8,自引:2,他引:6
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《The Journal of cell biology》1996,132(3):427-436
The extracellular domain of several membrane-anchored proteins can be released as a soluble fragment by the action of a cell surface endoproteolytic system. This cleavage results in the generation of a soluble and a cell-bound fragment. In the case of proteins with signaling capability, such as tyrosine kinase receptors, the cleavage process may have an effect on the kinase activity of the cell-bound receptor fragment. By using several cell lines that express the TrkA neurotrophin receptor, we show that this receptor tyrosine kinase is cleaved by a proteolytic system that mimics the one that acts at the cell surface. TrkA cleavage is regulated by protein kinase C and several receptor agonists (including the TrkA ligand NGF), occurs at the ectodomain in a membrane-proximal region, and is independent of lysosomal function. TrkA cleavage results in the generation of a cell- associated fragment that is phosphorylated on tyrosine residues. Tyrosine phosphorylation of this fragment is not detected in TrkA mutants devoid of kinase activity, suggesting that phosphorylation requires an intact TrkA kinase domain, and is not due to activation of an intermediate intracellular tyrosine kinase. The increased phosphotyrosine content of the cell-bound fragment may thus reflect higher catalytic activity of the truncated fragment. We postulate that cleavage of receptor tyrosine kinases by this naturally occurring cellular mechanism may represent an additional mean for the regulation of receptor activity. 相似文献
11.
Receptor tyrosine kinases (RTKs) are single-span transmembrane receptors in which relatively conserved intracellular kinase domains are coupled to divergent extracellular modules. The extracellular domains initiate receptor signaling upon binding to either soluble or membrane-embedded ligands. The diversity of extracellular domain structures allows for coupling of many unique signaling inputs to intracellular tyrosine phosphorylation. The combinatorial power of this receptor system is further increased by the fact that multiple ligands can typically interact with the same receptor. Such ligands often act as biased agonists and initiate distinct signaling responses via activation of the same receptor. Mechanisms behind such biased agonism are largely unknown for RTKs, especially at the level of receptor–ligand complex structure. Using recent progress in understanding the structures of active RTK signaling units, we discuss selected mechanisms by which ligands couple receptor activation to distinct signaling outputs. 相似文献
12.
Src kinase modulates the activation, transport and signalling dynamics of fibroblast growth factor receptors 总被引:1,自引:0,他引:1
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Sandilands E Akbarzadeh S Vecchione A McEwan DG Frame MC Heath JK 《EMBO reports》2007,8(12):1162-1169
The non-receptor tyrosine kinase Src is recruited to activated fibroblast growth factor receptor (FGFR) complexes through the adaptor protein factor receptor substrate 2 (FRS2). Here, we show that Src kinase activity has a crucial role in the regulation of FGFR1 signalling dynamics. Following receptor activation by ligand binding, activated Src is colocalized with activated FGFR1 at the plasma membrane. This localization requires both active Src and FGFR1 kinases, which are inter-dependent. Internalization of activated FGFR1 is associated with release from complexes containing activated Src. Src-mediated transport and subsequent activation of FGFR1 require both RhoB endosomes and an intact actin cytoskeleton. Chemical and genetic inhibition studies showed strikingly different requirements for Src family kinases in FGFR1-mediated signalling; activation of the phosphoinositide-3 kinase-Akt pathway is severely attenuated, whereas activation of the extracellular signal-regulated kinase pathway is delayed in its initial phase and fails to attenuate. 相似文献
13.
Mutating tyrosines 579 and 581 of the beta platelet-derived growth factor receptor (betaPDGFR) tyrosine kinase to phenylalanines (the F2 mutation) impair activation of the receptor in response to ligand, but mutation of the analogous tyrosines in the alphaPDGFR has no effect on ligand-dependent receptor activation. We have found that the F2 mutation has only a modest effect on ligand-dependent activation of a chimeric PDGFR composed of the extracellular and transmembrane domains of the alphaPDGFR and the cytoplasmic domain of the betaPDGFR by three measures: (1) the ability to phosphorylate endogenous and exogenous protein substrates in vitro, (2) phosphorylation of tyrosine 857, and (3) binding of the effector proteins PLCgamma, RasGAP, and SHP-2. Conversely, the F2 mutation substantially impairs ligand-dependent activation of chimeric PDGFRs that consist of either the extracellular domain alone or the extracellular and transmembrane domains of the betaPDGFR and all remaining sequence from the alphaPDGFR by two measures: (1) phosphorylation of endogenous protein substrates in vitro and (2) binding of PLCgamma and SHP-2. Our results indicate that the requirement of tyrosines 579 and 581 for maximal activation of the betaPDGFR in response to ligand is primarily determined by noncytoplasmic regions of the receptor. 相似文献
14.
Aberrant activation of the epidermal growth factor receptor (EGFR), a prototypic receptor tyrosine kinase, is critical to the biology of many common cancers. The molecular events that define how EGFR transmits an extracellular ligand binding event through the membrane are not understood. Here we use a chemical tool, bipartite tetracysteine display, to report on ligand-specific conformational changes that link ligand binding and kinase activation for full-length EGFR on the mammalian cell surface. We discover that EGF binding is communicated to the cytosol through formation of an antiparallel coiled coil within the intracellular juxtamembrane (JM) domain. This conformational transition is functionally coupled to receptor activation by EGF. In contrast, TGFα binding is communicated to the cytosol through formation of a discrete, alternative helical interface. These findings suggest that the JM region can differentially decode extracellular signals and transmit them to the cell interior. Our results provide new insight into how EGFR communicates ligand-specific information across the membrane. 相似文献
15.
二聚化:受体酪氨酸激酶活化的重要机制 总被引:1,自引:0,他引:1
受体酪氨酸激酶家族是一类具有内源性蛋白酪氨酸激酶活性的生长因子受体。它们具有相似的分子结构 ,其配体介导的受体活化主要是通过二聚化的机制来实现的。配体介导同源或异源的受体二聚化 ,不同的配体以不同的机制介导受体的二聚化。本文介绍了受体酪氨酸激酶家族不同亚类受体在其配体介导下二聚化的机制 ,并着重介绍了表皮生长因子受体家族各成员间的异二聚化及其引起的胞内信号转导途径的多样化 相似文献
16.
The transmembrane receptor 'ROR2' resembles members of the receptor tyrosine kinase family of signalling receptors in sequence but its' signal transduction mechanisms remain enigmatic. This problem has particular importance because mutations in ROR2 are associated with two human skeletal dysmorphology syndromes, recessive Robinow Syndrome (RS) and dominant acting Brachydactyly type B (BDB). Here we show, using a constitutive dimerisation approach, that ROR2 exhibits dimerisation-induced tyrosine kinase activity and the ROR2 C-terminal domain, which is deleted in BDB, is required for recruitment and activation of the non-receptor tyrosine kinase Src. Native ROR2 phosphorylation is induced by the ligand Wnt5a and is blocked by pharmacological inhibition of Src kinase activity. Eight sites of Src-mediated ROR2 phosphorylation have been identified by mass spectrometry. Activation via tyrosine phosphorylation of ROR2 receptor leads to its internalisation into Rab5 positive endosomes. These findings show that BDB mutant receptors are defective in kinase activation as a result of failure to recruit Src. 相似文献
17.
Receptor tyrosine kinases (RTKs) activate downstream signaling through cognate growth factor receptor-induced dimerization and autophosphorylation. Overexpression of RTKs can lead to constitutive activation due to increased dimerization in the absence of ligand, and downstream signals are presumed to be the same as the ligand-induced signals. We have shown that the murine Ron (mRon) receptor tyrosine kinase exhibits constitutive activation of the MAP kinase pathway that is independent of the two docking site tyrosines, whereas activation of this pathway in response to ligand (macrophage-stimulating protein) is abolished in the absence of these tyrosines. Furthermore, we identified three tyrosines (Tyr-1175, Tyr-1265, and Tyr-1294) within the kinase domain that play critical but overlapping roles in controlling constitutive Erk activation by mRon. Phenylalanine mutations at these three tyrosines results in a receptor that fails to constitutively activate the Erk pathway but retains the ability to induce Erk phosphorylation in response to ligand stimulation. The ability of mRon to activate the MAP kinase pathway is dependent on c-Src activity, and we have shown that c-Src co-immunoprecipitates with mRon. c-Src fails to interact with mRon when the three tyrosines required for MAP kinase activation are mutated, whereas the presence of any one of these tyrosines alone restores Erk phosphorylation and recruitment of c-Src. Thus, the ligand-dependent and -independent activity of mRon can be uncoupled through the alteration of selective sets of tyrosines. 相似文献
18.
A sequence motif in the transmembrane region of growth factor receptors with tyrosine kinase activity mediates dimerization 总被引:16,自引:0,他引:16
A mechanism by which ligand binding to the extracellular domain of a growth factor receptor causes activation of its cytoplasmic tyrosine kinase domain is that binding promotes receptor dimerization. Recently we proposed a model in which dimerization of the transmembrane alpha-helices in one member of this family, rat neu, is mediated by the presence of three specific residues. This paper shows that a similar sequence motif is observed in 18 of the 20 transmembrane alpha-helices of the tyrosine kinase family of growth factor receptors. The motif encompasses a five residue segment in which position 0 (P0) requires a small side chain (Gly, Ala, Ser, Thr or Pro), P3 an aliphatic side chain (Ala, Val, Leu or Ile) and P4 only the smallest side chains (Gly or Ala). In addition other features of the transmembrane sequences are reported. It is concluded that the dimerization of transmembrane alpha-helices may be a general mechanism of tyrosine kinase activation in this family of growth factor receptors. 相似文献
19.
Meghan McCabe Pryor Mara P. Steinkamp Adam M. Halasz Ye Chen Shujie Yang Marilyn S. Smith Gergely Zahoransky-Kohalmi Mark Swift Xiao-Ping Xu Dorit Hanien Niels Volkmann Diane S. Lidke Jeremy S. Edwards Bridget S. Wilson 《Molecular biology of the cell》2015,26(22):4109-4123
Members of the ErbB family of receptor tyrosine kinases are capable of both homointeractions and heterointeractions. Because each receptor has a unique set of binding sites for downstream signaling partners and differential catalytic activity, subtle shifts in their combinatorial interplay may have a large effect on signaling outcomes. The overexpression and mutation of ErbB family members are common in numerous human cancers and shift the balance of activation within the signaling network. Here we report the development of a spatial stochastic model that addresses the dynamics of ErbB3 homodimerization and heterodimerization with ErbB2. The model is based on experimental measures for diffusion, dimer off-rates, kinase activity, and dephosphorylation. We also report computational analysis of ErbB3 mutations, generating the prediction that activating mutations in the intracellular and extracellular domains may be subdivided into classes with distinct underlying mechanisms. We show experimental evidence for an ErbB3 gain-of-function point mutation located in the C-lobe asymmetric dimerization interface, which shows enhanced phosphorylation at low ligand dose associated with increased kinase activity. 相似文献
20.
Margret S. Fernandes Mamatha M. Reddy Nicole J. Croteau Christoph Walz Henry Weisbach Klaus Podar Hamid Band Martin Carroll Andreas Reiter Richard A. Larson Ravi Salgia James D. Griffin Martin Sattler 《The Journal of biological chemistry》2010,285(42):32596-32605
Acute myeloid leukemia (AML) is characterized by multiple mutagenic events that affect proliferation, survival, as well as differentiation. Recently, gain-of-function mutations in the α helical structure within the linker sequence of the E3 ubiquitin ligase CBL have been associated with AML. We identified four novel CBL mutations, including a point mutation (Y371H) and a putative splice site mutation in AML specimens. Characterization of these two CBL mutants revealed that coexpression with the receptor tyrosine kinases FLT3 (Fms-like tyrosine kinase 3) or KIT-induced ligand independent growth or ligand hyperresponsiveness, respectively. Growth of cells expressing mutant CBL required expression and kinase activity of FLT3. In addition to the CBL-dependent phosphorylation of FLT3 and CBL itself, transformation was associated with activation of Akt and STAT5 and required functional expression of the small GTPases Rho, Rac, and Cdc42. Furthermore, the mutations led to constitutively elevated intracellular reactive oxygen species levels, which is commonly linked to increased glucose metabolism in cancer cells. Inhibition of hexokinase with 2-deoxyglucose blocked the transforming activity of CBL mutants and reduced activation of signaling mechanisms. Overall, our data demonstrate that mutations of CBL alter cellular biology at multiple levels and require not only the activation of receptor proximal signaling events but also an increase in cellular glucose metabolism. Pathways that are activated by CBL gain-of-function mutations can be efficiently targeted by small molecule drugs. 相似文献