Growth factors: Difference between revisions
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The <scene name='80/801744/Cv/4'>kinase domain of M-CSF receptor interacts with a drug-designed inhibitor</scene> via the conserved kinase DFG motif (colored in salmon) and its gatekeeper threonine residue (colored in magenta)<ref>PMID:23493555</ref>. | The <scene name='80/801744/Cv/4'>kinase domain of M-CSF receptor interacts with a drug-designed inhibitor</scene> via the conserved kinase DFG motif (colored in salmon) and its gatekeeper threonine residue (colored in magenta)<ref>PMID:23493555</ref>. | ||
*[[Epidermal growth factor]] and [[Epidermal Growth Factor Receptor]] (EGFR). EGFR belongs to [[Receptor tyrosine kinases]], class I. | *[[Epidermal growth factor]] and [[Epidermal Growth Factor Receptor]] (EGFR). EGFR belongs to [[Receptor tyrosine kinases]], class I. | ||
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See also [[Herceptin - Mechanism of Action]] | See also [[Herceptin - Mechanism of Action]] | ||
*[[Ephrin]] and [[Ephrin receptor]] | *[[Ephrin]] and [[Ephrin receptor]]. Ephrin belongs to Receptor tyrosine kinases, class IX. | ||
'''Ephrins''' (Eph) are the membrane-bound ligands of ephrin receptors. | '''Ephrins''' (Eph) are the membrane-bound ligands of ephrin receptors. The binding of Eph and ephrin receptors is achieved via cell-cell interaction. Eph/Eph receptor signaling regulates embryonic development, guidance of axon growth, long-term potentiation, angiogenesis and stem-cell differentiation <ref>PMID:17420126</ref>. Eph-A5 is implicated in spinal cord injury. Eph-A1 is implicated in myocardial injury and renal reperfusion injury. <scene name='59/594659/Cv/4'>Ephrin-A5 receptor-binding domain complex with ephrin type A receptor 2</scene> (PDB code [[3mx0]]).<ref>PMID:20505120</ref> | ||
<scene name='45/450911/Cv/8'>Ephrin A3 receptor with peptide substrate, nucleotide derivative and Mg+2 ion</scene>. Water molecules are shown as red spheres. | <scene name='45/450911/Cv/8'>Ephrin A3 receptor with peptide substrate, nucleotide derivative and Mg+2 ion</scene>. Water molecules are shown as red spheres. | ||
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*[[Growth differentiation factor]] | *[[Growth differentiation factor]] | ||
For more details see [[Group:MUZIC:Myostatin]]. See also [[Bone morphogenetic protein]]. | For more details see [[Group:MUZIC:Myostatin]]. See also [[Bone morphogenetic protein]]. | ||
*[[Hepatocyte growth factor]] and [[Hepatocyte growth factor receptor]] | *[[Hepatocyte growth factor]] and [[Hepatocyte growth factor receptor]] (HGFR). HGFR belongs to Receptor tyrosine kinases, class VIII. | ||
The A loop of the wt receptor contains 2 tyrosines at position 1234 and 1235. When these 2 residues become phosphorylated, the kinase can become active. A unique part of the c-met structure is the pair of <scene name='Hepatocyte_growth_factor_receptor/Tyrisine_docking_sites/1'>tyrosine residues (1349 and 1356)</scene>. These tyrosines are necessary for normal c-met signaling. When these 2 tyrosines were substituted with with phenylalanine in mice, the mice had an embryonically lethal phenotype and defects were found in placenta, liver, muscles and nerves. In a wt c-met, these sites will become phosphorylated and act as docking sites for many different transducers and adapters. Upon phosphorylation, these tyrosines can bind with Src homology 2 (SH2) domains and phophotyrosine-binding (PTB), and therefore bind many effectors that will cause downstream effects such as cell proliferation, scattering and inhibition of apoptosis. This receptor follows the typical structure of a protein kinase, with a bilobal structure. The N-terminal contains <scene name='Hepatocyte_growth_factor_receptor/Beta_sheets/1'>β-sheets</scene> and is linked through a hinge to the C lobe, which is full of α helices. This particular kinase domain is very similar to the domains of the insulin receptor kinase and fibroblast growth factor receptor kinase.<ref>PMID: 14559966</ref> This structure is made up of many α-helices that move in the transformation from inactive to active kinase. Some of these helices are conserved in many different tyrosine kinases. C-met does show a divergence from other tyrosine kinases (such as IRK and FGFRK) in the helix formed at the N-terminus, before the core kinase domain, in residues <scene name='Hepatocyte_growth_factor_receptor/1060-1069/1'>1060-1069</scene>. The αA is in contact with αC and so causes αC to be in a slightly different orientation than in FGFRK and IRK. Residues Leu-1062, Val-1066, and Val-1069 of αA <scene name='Hepatocyte_growth_factor_receptor/A_and_c_intercalating/1'>intercalate</scene> with with residues Leu-1125 and Ile-1129 of αC. There is another <scene name='Hepatocyte_growth_factor_receptor/A_and_c_intercalating/2'>interaction</scene> between the residues Ile-1053, Leu-1055 and Leu-1058 of αA and Ile-1118 and Val-1121 of αC. Because of the movement of αC during activation of the kinase, it is an assumption that αA is also part of the kinase activation upon ligand binding. | The A loop of the wt receptor contains 2 tyrosines at position 1234 and 1235. When these 2 residues become phosphorylated, the kinase can become active. A unique part of the c-met structure is the pair of <scene name='Hepatocyte_growth_factor_receptor/Tyrisine_docking_sites/1'>tyrosine residues (1349 and 1356)</scene>. These tyrosines are necessary for normal c-met signaling. When these 2 tyrosines were substituted with with phenylalanine in mice, the mice had an embryonically lethal phenotype and defects were found in placenta, liver, muscles and nerves. In a wt c-met, these sites will become phosphorylated and act as docking sites for many different transducers and adapters. Upon phosphorylation, these tyrosines can bind with Src homology 2 (SH2) domains and phophotyrosine-binding (PTB), and therefore bind many effectors that will cause downstream effects such as cell proliferation, scattering and inhibition of apoptosis. This receptor follows the typical structure of a protein kinase, with a bilobal structure. The N-terminal contains <scene name='Hepatocyte_growth_factor_receptor/Beta_sheets/1'>β-sheets</scene> and is linked through a hinge to the C lobe, which is full of α helices. This particular kinase domain is very similar to the domains of the insulin receptor kinase and fibroblast growth factor receptor kinase.<ref>PMID: 14559966</ref> This structure is made up of many α-helices that move in the transformation from inactive to active kinase. Some of these helices are conserved in many different tyrosine kinases. C-met does show a divergence from other tyrosine kinases (such as IRK and FGFRK) in the helix formed at the N-terminus, before the core kinase domain, in residues <scene name='Hepatocyte_growth_factor_receptor/1060-1069/1'>1060-1069</scene>. The αA is in contact with αC and so causes αC to be in a slightly different orientation than in FGFRK and IRK. Residues Leu-1062, Val-1066, and Val-1069 of αA <scene name='Hepatocyte_growth_factor_receptor/A_and_c_intercalating/1'>intercalate</scene> with with residues Leu-1125 and Ile-1129 of αC. There is another <scene name='Hepatocyte_growth_factor_receptor/A_and_c_intercalating/2'>interaction</scene> between the residues Ile-1053, Leu-1055 and Leu-1058 of αA and Ile-1118 and Val-1121 of αC. Because of the movement of αC during activation of the kinase, it is an assumption that αA is also part of the kinase activation upon ligand binding. | ||
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*[[Insulin]] and [[Insulin receptor]]. Insulin receptor belongs to [[Receptor tyrosine kinases]], class II. | *[[Insulin]] and [[Insulin receptor]]. Insulin receptor belongs to [[Receptor tyrosine kinases]], class II. | ||
*[[Insulin-like growth factor]] and [[Insulin-like growth factor receptor]] | *[[Insulin-like growth factor]] and [[Insulin-like growth factor receptor]] | ||
Memory-Enhancement by Traditional Chinese Medicine? <ref>doi 10.1080/07391102.2012.741052</ref> | |||
<scene name='Journal:JBSD:38/Cv/3'>IGF receptor </scene> (IGF-IR, in darkmagenta) activation is critical for IGF-I to elicit desirable cognitive functions. Molecular dynamics simulation revealed that the Traditional Chinese medicine (TCM) ligands were secured at the opening of the IGF-IR binding site for the duration of the MD. <scene name='Journal:JBSD:38/Cv/7'>3-(2-carboxyphenyl)-4(3H)-quinazolinone</scene> was stabilized by <scene name='Journal:JBSD:38/Cv/8'>Asp1056</scene>, <scene name='Journal:JBSD:38/Cv/9'>(+)-N-methyllaurotetanine</scene> was stabilized by <scene name='Journal:JBSD:38/Cv/10'>Leu975 and Asp1056</scene>, and <scene name='Journal:JBSD:38/Cv/11'>(+)-1(R)-Coclaurine</scene> was stabilized by <scene name='Journal:JBSD:38/Cv/12'>Leu975 and Gly1055</scene> (key residues are colored in yellow). | |||
**[[IGF1]] | **[[IGF1]] | ||
*[[Interleukin]] | *[[Interleukin]] | ||
*[[Neurotrophin]] | '''Interleukin''' (IL) is a cytokine which functions in the immune system. IL families are denoted by numbers<ref>PMID:3277884</ref>.<br /> | ||
'''IL-1''' is a group of 11 cytokines which regulate immune and inflammatory response. See [[Interleukin-1 beta]].<br /> | |||
'''IL-2''' is a cytokine made by leukocytes. It is used in cancer therapy to boost the immune system.<br /> | |||
'''IL-3''' improves the body's natural response to disease by stimulating the differentiation of multipotent hematopoietic stem cells into myeloid or lymphoid progenitor cells.<br /> | |||
'''IL-4''' induces the differentiation of naive helper T cells (Th0) to Th2 cells.<br /> | |||
'''IL-5''' stimulates B cell growth and increases immunoglobulin secretion.<br /> | |||
'''IL-6''' is both a pro-inflammatory cytokine and anti-inflammatory myokine.<br /> | |||
'''IL-7''' is a cytokine important for B and T cells development.<br /> | |||
'''IL-8''' induces chemotaxis and phagocytosis.<br /> | |||
'''IL-10''' see [[Interleukin-10]] and [[Inflammation & Rheumatoid Arthritis]].<br /> | |||
'''IL-11''' involved in the stimulation of megakaryocyte maturation.<br /> | |||
''' IL-12''' induces the differentiation of naive helper T cells (Th0) to Th1 cells. See [[Interleukin-12]].<br /> | |||
'''IL-13''' induces the differentiation of naive helper T cells (Th0) to Th2 cells.<br /> | |||
'''IL-15''' see [[Interleukin-15]].<br /> | |||
'''IL-16''' acts as chemoattractant, modulator of T cell activity and inhibitor of HIV replication.<br /> | |||
'''IL-17''' recruits monocytes and neutrophils to the site of inflammation.<br /> | |||
'''IL-18''' induces cell-mediated immunity following infection by microbial lipopolysaccharides.<br /> | |||
'''IL-19''' induces activation of the signal transducer and activator of STAT3.<br /> | |||
''' IL-21''' has potent effect on natural killer cells.<br /> | |||
'''IL-22''' stimulates inflammatory responses like S100 and defensin.<br /> | |||
''' IL-23''' induces activation of the signal transducer and activator of STAT4.<br /> | |||
''' IL-24''' induces activation of the signal transducer and activator of STAT1 and STAT3.<br /> | |||
'''IL-28''' has a role in the immune defense against viruses.<br /> | |||
'''IL-29''' similar to IL-28.<br /> | |||
'''IL-33''' induces helper T cells, mast cells, eosinophils and basophils to produce type 2 cytokines.<br /> | |||
'''IL-34''' increases growth or survival of monocytes.<br /> | |||
'''IL-36''' acts on naïve CD4+ T cells.<br /> | |||
''' IL-37''' has a role in inhibiting both innate and adaptive immune responses.<br /> | |||
*[[Neurotrophin|Neurotrophin & its receptor]] | |||
The complex between NT3 and p75 neurotrophin receptor (p75NTR) shows a <scene name='80/805035/Cv/2'>homodimer of NT3 with two symmetrically arranged p75NTR molecules</scene>. There are 3 sites of interactions between NT3 and p75NTR - site 1, site 2 and site 3. | |||
<scene name='80/805035/Cv/3'>Site 1</scene>. | |||
<scene name='80/805035/Cv/4'>Site 2</scene>. | |||
<scene name='80/805035/Cv/5'>Site 3</scene>. | |||
**[[High affinity nerve growth factor receptor]] | **[[High affinity nerve growth factor receptor]] | ||
'''TrkA'''. Trk stands for Topomyosin-Related Kinase. TrkA ligand - nerve growth factor activates the receptor by stabilizing homodimer formation which initiates transautophosphorylation. <scene name='80/805001/Cv/4'>Structure of Nerve Growth Factor Complexed with the Extracellular Domain of TrkA</scene>. An <scene name='80/805001/Cv/7'>Arg residue</scene>, conserved in all neutrophins, forms the most important binding determinant between TrkA and its ligand - nerve growth factor - which forms the active homodimer of the receptor. <scene name='80/805001/Cv/6'>All interactions between TrkA chain A and NGF</scene>. | |||
**[[Tyrosine kinase receptor|Tyrosine kinase receptor TrkA]] | |||
TRK-A contains an extracellular ligand binding domain (LBD), a transmembrane helix and an intracellular region which contains the kinase domain. The kinase domain ([[4yne]]) contains the tripeptide DFG which flips out in TRK-A inactivated form. <scene name='83/839914/Cv/7'>Inhibitor binding site</scene> ([[4yne]]). The structure of the complex of TRK-A with the phenylpyrrolidine derivative shows the inhibitor forming hydrogen bonds to Met620 and Lys572 residues and π-π interactions of it with Phe617 and Phe 698. | |||
The <scene name='83/839914/Cv/4'>complex between TRK-A and the nerve growth factor</scene> ([[2ifg]]) is a 2:2 dimer. The C-terminal immunoglobulin-like domain interacts with the NGF. The extracellular domain of TRK-A contains <scene name='83/839914/Cv/5'>3 Leu-rich regions</scene> flanked by <scene name='83/839914/Cv/6'>Cys-rich regions</scene> (in yellow), 2 immunoglobulin-like domains and the nerve growth factor (NGF) binding domain. | |||
**[[TrkB tyrosine kinase receptor]] | **[[TrkB tyrosine kinase receptor]] | ||
<scene name='80/805008/Cv/6'>Structure of the TrkB-d5:NT-4/5 Complex, comprising one homodimer of NT-4/5 bound to two monomers of TrkB-d5</scene>. TrkB and neutrotrophin-4/5 interact via a <scene name='80/805008/Cv/7'>specificity interaction site</scene> and via a <scene name='80/805008/Cv/8'>conserved interaction site</scene>. | |||
*[[Platelet-derived growth factors and receptors]]. Platelet-derived growth factor receptor belongs to [[Receptor tyrosine kinases]], class III. | *[[Platelet-derived growth factors and receptors]]. Platelet-derived growth factor receptor belongs to [[Receptor tyrosine kinases]], class III. | ||
*[[ | *[[Tumor necrosis factor]] and [[Tumor necrosis factor ligand superfamily]] | ||
The biological assembly of human tumor necrosis factor is <scene name='55/551212/Cv/4'>homotetramer</scene> (PDB entry [[2az5]]). <scene name='55/551212/Cv/5'>Inhibitor binding site</scene>. | |||
**[[TRAIL|TRAIL (TNF-related apoptosis-inducing ligand) or TNF ligand superfamily 10]] | |||
'''TRAIL-R2''' is called '''DR5'''. <scene name='48/480878/Cv/3'>TRAIL trimer residues complex with death receptor-5 extracellular domain</scene> ([[1d0g]]). | |||
**[[Tumor necrosis factor receptor]] | **[[Tumor necrosis factor receptor]] | ||
The extracellular domain of TNFR contains 2 to 6 cysteine-rich domains (CRD). The <scene name='59/590824/Cv/8'>CRD domains are ca. 40 amino-acid long and contain 4-6 cysteine residues</scene>. The CRDs are involved in binding of TNF<ref>PMID:8939750</ref>. <scene name='59/590824/Cv/9'>Mg coordination site</scene>. Water molecules are shown as red spheres. | |||
*[[Vascular Endothelial Growth Factor]] and [[Vascular Endothelial Growth Factor Receptor]] (VEGFR). VEGFR belongs to [[Receptor tyrosine kinases]], class IV. | *[[Vascular Endothelial Growth Factor]] and [[Vascular Endothelial Growth Factor Receptor]] (VEGFR). VEGFR belongs to [[Receptor tyrosine kinases]], class IV. | ||
<scene name='Vascular_Endothelial_Growth_Factor/Vegf-a_opening/1'>VEGF-A</scene> is a homodimer composed of two 23 kDa subunits. VEGF-A exists in a number of different isoforms following alternative splicing of its precursor mRNA <ref>PMID: 11181169</ref>. In humans, 6 variants have been found: VEGF-A-121, VEGF-A-145, VEGF-A-165, VEGF-A-183, VEGF-A-189, and VEGF-A-206, with VEGF-A-165 the most abundantly expressed. All VEGF-A isoforms bind to VEGFR-1 and -2. | |||
The amino acids determined to be <scene name='Vascular_Endothelial_Growth_Factor/Vegf-a_binding_to_vegfr1/2'>critical to binding to VEGFR-1</scene> are D63, L66, and E67. VEGF-A binding by VEGFR-1 leads to cellular proliferation, migration, and increased cellular permeability resulting in vasculogenesis and angiogenesis. Those residues <scene name='Vascular_Endothelial_Growth_Factor/Vegf-a_binding_to_vegfr2/2'>critical to binding to VEGFR-2</scene> are I43, I46, Q79, I83, K84 and P85.<ref>pmid:9207067</ref> Binding of VEGF-A to VEGFR-2 results in similar Vasculogenesis and angiogenesis, but also lymphangiogenesis in embryos. The remainder of the <scene name='Vascular_Endothelial_Growth_Factor/Vegf-a_full_binding_site/1'>binding pocket </scene> is formed by D34, S50, E64, and F36. It is upon binding of VEGFR by VEGF that the subsequent signal cascade is initiated leading to angiogenesis, etc.<ref>pmid:8621427</ref> | |||
<scene name='Vascular_Endothelial_Growth_Factor/Vegf-e_opening/1'>VEGF-E</scene> consists of a homodimer that is covalently linked by two intermolecular disulfide bonds between <scene name='41/411433/Cys51-cys60/1'>Cys51 and Cys 60</scene>. | |||
Each monomer contains a central antiparallel beta sheet, with the canonical <scene name='41/411433/Knot_new/3'>cysteine knot </scene> found in other VEGFs. <ref>PMID:1396586</ref> The knot consists of an eight residue ring formed by the backbone of residues 57-61 and 102-104 and intramolecular disulfide bridges Cys57-Cys102 and Cys61-Cys104, and a third bridge, Cys26-Cys68, that passes perpendicularly through the ring. Each VEGF-E monomer contains an amino terminal alpha helix and three solvent accessible loop regions, L2, <scene name='41/411433/Vegf-e_l1_l3/3'>L1 and L3 </scene>. | |||
are able to form a complex hydrogen bond network as well as extensive hydrophobic contacts with VEGFR making these loops ideal receptor specificity determinants. Residues: P34, S36, T43, P50, R46, D63, E64, and E67 make up the <scene name='Vascular_Endothelial_Growth_Factor/Vegf-e_binding_site/1'>VEGF-E binding pocket </scene>and are critical for binding to VEGFR-2 as determined by alanine mutagenesis.<ref> PMID:16672228</ref> Further, the salt bridge between <scene name='41/411433/Vegf-e_salt_bridge/4'>R46 and E64 </scene> is believed to be the source of VEGF-E’s VEGFR-2 specificity by preventing binding to VEGFR-1. <ref>PMID:15272021</ref> | |||
[[Vascular Endothelial Growth Factor Receptor]]s (VEGFRs) are [[tyrosine kinase receptors]] responsible for binding with [[VEGF]] to initiate signal cascades that stimulate angiogenesis among other effects. The tyrosine kinase domain of VEGFR-2 is separated into 2 segments with a 70 amino acid long kinase insert region. Upon binding VEGFA and subsequent dimerization, VEGFR-2 is autophosphoryalted at the carboxy terminal tail and kinase insert region, 6 tyrosine residues of VEGFR2 are autophosphorylated. <scene name='41/411436/Cv/2'>Auto-phosphorylation of residues 1054 and 1059</scene> within the activation loop of VEGFR2 leads to increased kinase activity. <scene name='41/411436/Cv/4'>Anti-tumor inhibitor binding site</scene> ([[3c7q]]). | |||
See also [[Bevacizumab]]. | |||
*[[TGF-beta receptor|Transforming Growth Factor and its receptor]] | *[[TGF-beta receptor|Transforming Growth Factor and its receptor]] | ||
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*[[Receptor]] | *[[Receptor]] | ||
*[[Receptor tyrosine kinases]] | *[[Receptor tyrosine kinases]] | ||
*[[Cancer]] | |||
</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
<references/> | <references/> | ||