6lvm

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Crystal structure of FGFR3 in complex with pyrimidine derivative

Structural highlights

6lvm is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.53Å
Ligands:EVR, PTR
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

FGFR3_HUMAN Defects in FGFR3 are the cause of achondroplasia (ACH) [MIM:100800. ACH is an autosomal dominant disease and is the most frequent form of short-limb dwarfism. It is characterized by a long, narrow trunk, short extremities, particularly in the proximal (rhizomelic) segments, a large head with frontal bossing, hypoplasia of the midface and a trident configuration of the hands.[1] [2] [3] [4] [5] [6] Defects in FGFR3 are the cause of Crouzon syndrome with acanthosis nigricans (CAN) [MIM:612247. Classic Crouzon disease which is caused by mutations in the FGFR2 gene is characterized by craniosynostosis (premature fusion of the skull sutures), and facial hypoplasia. Crouzon syndrome with acanthosis nigricans (a skin disorder characterized by pigmentation anomalies), CAN, is considered to be an independent disorder from classic Crouzon syndrome. CAN is characterized by additional more severe physical manifestation, such as Chiari malformation, hydrocephalus, and atresia or stenosis of the choanas, and is caused by a specific mutation (Ala-391 to Glu) in the transmembrane domain of FGFR3. It is proposed to have an autosomal dominant mode of inheritance.[7] [8] [9] [10] [11] Defects in FGFR3 are a cause of thanatophoric dysplasia type 1 (TD1) [MIM:187600; also known as thanatophoric dwarfism or platyspondylic lethal skeletal dysplasia Sand Diego type (PLSD-SD). TD1 is the most common neonatal lethal skeletal dysplasia. Affected individuals display features similar to those seen in homozygous achondroplasia. It causes severe shortening of the limbs with macrocephaly, narrow thorax and short ribs. In the most common subtype, TD1, femur are curved.[12] [13] [14] [15] [16] [17] Defects in FGFR3 are a cause of thanatophoric dysplasia type 2 (TD2) [MIM:187601. It is a neonatal lethal skeletal dysplasia causing severe shortening of the limbs, narrow thorax and short ribs. Patients with thanatophoric dysplasia type 2 have straight femurs and cloverleaf skull. Defects in FGFR3 are a cause of hypochondroplasia (HCH) [MIM:146000. HCH is an autosomal dominant disease and is characterized by disproportionate short stature. It resembles achondroplasia, but with a less severe phenotype. Defects in FGFR3 are a cause of susceptibility to bladder cancer (BLC) [MIM:109800. A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas. They begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. Note=Somatic mutations can constitutively activate FGFR3. Defects in FGFR3 are a cause of cervical cancer (CERCA) [MIM:603956. A malignant neoplasm of the cervix, typically originating from a dysplastic or premalignant lesion previously present at the active squamocolumnar junction. The transformation from mild dysplastic to invasive carcinoma generally occurs slowly within several years, although the rate of this process varies widely. Carcinoma in situ is particularly known to precede invasive cervical cancer in most cases. Cervical cancer is strongly associated with infection by oncogenic types of human papillomavirus. Defects in FGFR3 are the cause of camptodactyly tall stature and hearing loss syndrome (CATSHL syndrome) [MIM:610474. CATSHL syndrome is an autosomal dominant syndrome characterized by permanent and irreducible flexion of one or more fingers of the hand and/or feet, tall stature, scoliosis and/or a pectus excavatum, and hearing loss. Affected individuals have developmental delay and/or mental retardation, and several of these have microcephaly. Radiographic findings included tall vertebral bodies with irregular borders and broad femoral metaphyses with long tubular shafts. On audiological exam, each tested member have bilateral sensorineural hearing loss and absent otoacoustic emissions. The hearing loss was congenital or developed in early infancy, progressed variably in early childhood, and range from mild to severe. Computed tomography and magnetic resonance imaging reveal that the brain, middle ear, and inner ear are structurally normal. Defects in FGFR3 are a cause of multiple myeloma (MM) [MIM:254500. MM is a malignant tumor of plasma cells usually arising in the bone marrow and characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria and anemia. Complications of multiple myeloma are bone pain, hypercalcemia, renal failure and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. Amyloidosis may develop in some patients. Multiple myeloma is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. Note=A chromosomal aberration involving FGFR3 is found in multiple myeloma. Translocation t(4;14)(p16.3;q32.3) with the IgH locus. Defects in FGFR3 are a cause of lacrimo-auriculo-dento-digital syndrome (LADDS) [MIM:149730; also known as Levy-Hollister syndrome. LADDS is a form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. LADDS is an autosomal dominant syndrome characterized by aplastic/hypoplastic lacrimal and salivary glands and ducts, cup-shaped ears, hearing loss, hypodontia and enamel hypoplasia, and distal limb segments anomalies. In addition to these cardinal features, facial dysmorphism, malformations of the kidney and respiratory system and abnormal genitalia have been reported. Craniosynostosis and severe syndactyly are not observed.[18] Defects in FGFR3 are a cause of keratinocytic non-epidermolytic nevus (KNEN) [MIM:162900; also known as pigmented moles. Epidermal nevi of the common, non-organoid and non-epidermolytic type are benign skin lesions and may vary in their extent from a single (usually linear) lesion to widespread and systematized involvement. They may be present at birth or develop early during childhood.[19] Defects in FGFR3 are a cause of Muenke syndrome (MNKS) [MIM:602849; also known as Muenke non-syndromic coronal craniosynostosis. MNKS is a condition characterized by premature closure of coronal suture of skull during development (coronal craniosynostosis), which affects the shape of the head and face. It may be uni- or bilateral. When bilateral, it is characterized by a skull with a small antero-posterior diameter (brachycephaly), often with a decrease in the depth of the orbits and hypoplasia of the maxillae. Unilateral closure of the coronal sutures leads to flattening of the orbit on the involved side (plagiocephaly). The intellect is normal. In addition to coronal craniosynostosis some affected individuals show skeletal abnormalities of hands and feet, sensorineural hearing loss, mental retardation and respiratory insufficiency.[20] [21] [22] Defects in FGFR3 are a cause of keratosis seborrheic (KERSEB) [MIM:182000. A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance.[23] Defects in FGFR3 may be a cause of testicular germ cell tumor (TGCT) [MIM:273300. A common solid malignancy in males. Germ cell tumors of the testis constitute 95% of all testicular neoplasms.[24]

Function

FGFR3_HUMAN Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays an essential role in the regulation of chondrocyte differentiation, proliferation and apoptosis, and is required for normal skeleton development. Regulates both osteogenesis and postnatal bone mineralization by osteoblasts. Promotes apoptosis in chondrocytes, but can also promote cancer cell proliferation. Required for normal development of the inner ear. Phosphorylates PLCG1, CBL and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Plays a role in the regulation of vitamin D metabolism. Mutations that lead to constitutive kinase activation or impair normal FGFR3 maturation, internalization and degradation lead to aberrant signaling. Over-expressed or constitutively activated FGFR3 promotes activation of PTPN11/SHP2, STAT1, STAT5A and STAT5B.[25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36]

Publication Abstract from PubMed

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer. We identified 1,3,5-triazine derivative 18b and pyrimidine derivative 40a as novel structures with potent and highly selective FGFR3 inhibitory activity over vascular endothelial growth factor receptor 2 (VEGFR2) using a structure-based drug design (SBDD) approach. X-ray crystal structure analysis suggests that interactions between 18b and amino acid residues located in the solvent region (Lys476 and Met488), and between 40a and Met529 located in the back pocket of FGFR3 may underlie the potent FGFR3 inhibitory activity and high kinase selectivity over VEGFR2.

Structure-based drug design of 1,3,5-triazine and pyrimidine derivatives as novel FGFR3 inhibitors with high selectivity over VEGFR2.,Kuriwaki I, Kameda M, Hisamichi H, Kikuchi S, Iikubo K, Kawamoto Y, Moritomo H, Kondoh Y, Amano Y, Tateishi Y, Echizen Y, Iwai Y, Noda A, Tomiyama H, Suzuki T, Hirano M Bioorg Med Chem. 2020 May 15;28(10):115453. doi: 10.1016/j.bmc.2020.115453. Epub , 2020 Mar 28. PMID:32278710[37]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
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Computational anti-COVID-19 drug design: progress and challenges.
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See Also

References

  1. ↑ Monsonego-Ornan E, Adar R, Feferman T, Segev O, Yayon A. The transmembrane mutation G380R in fibroblast growth factor receptor 3 uncouples ligand-mediated receptor activation from down-regulation. Mol Cell Biol. 2000 Jan;20(2):516-22. PMID:10611230
  2. ↑ Monsonego-Ornan E, Adar R, Rom E, Yayon A. FGF receptors ubiquitylation: dependence on tyrosine kinase activity and role in downregulation. FEBS Lett. 2002 Sep 25;528(1-3):83-9. PMID:12297284
  3. ↑ Rousseau F, Bonaventure J, Legeai-Mallet L, Pelet A, Rozet JM, Maroteaux P, Le Merrer M, Munnich A. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature. 1994 Sep 15;371(6494):252-4. PMID:8078586 doi:http://dx.doi.org/10.1038/371252a0
  4. ↑ Bellus GA, Hefferon TW, Ortiz de Luna RI, Hecht JT, Horton WA, Machado M, Kaitila I, McIntosh I, Francomano CA. Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am J Hum Genet. 1995 Feb;56(2):368-73. PMID:7847369
  5. ↑ Superti-Furga A, Eich G, Bucher HU, Wisser J, Giedion A, Gitzelmann R, Steinmann B. A glycine 375-to-cysteine substitution in the transmembrane domain of the fibroblast growth factor receptor-3 in a newborn with achondroplasia. Eur J Pediatr. 1995 Mar;154(3):215-9. PMID:7758520
  6. ↑ Webster MK, Donoghue DJ. Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia. EMBO J. 1996 Feb 1;15(3):520-7. PMID:8599935
  7. ↑ Meyers GA, Orlow SJ, Munro IR, Przylepa KA, Jabs EW. Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nat Genet. 1995 Dec;11(4):462-4. PMID:7493034 doi:http://dx.doi.org/10.1038/ng1295-462
  8. ↑ Cappellen D, De Oliveira C, Ricol D, de Medina S, Bourdin J, Sastre-Garau X, Chopin D, Thiery JP, Radvanyi F. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet. 1999 Sep;23(1):18-20. PMID:10471491 doi:10.1038/12615
  9. ↑ Jang JH, Shin KH, Park JG. Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers. Cancer Res. 2001 May 1;61(9):3541-3. PMID:11325814
  10. ↑ Sibley K, Cuthbert-Heavens D, Knowles MA. Loss of heterozygosity at 4p16.3 and mutation of FGFR3 in transitional cell carcinoma. Oncogene. 2001 Feb 8;20(6):686-91. PMID:11314002 doi:10.1038/sj.onc.1204110
  11. ↑ Arnaud-Lopez L, Fragoso R, Mantilla-Capacho J, Barros-Nunez P. Crouzon with acanthosis nigricans. Further delineation of the syndrome. Clin Genet. 2007 Nov;72(5):405-10. PMID:17935505 doi:CGE884
  12. ↑ Tavormina PL, Rimoin DL, Cohn DH, Zhu YZ, Shiang R, Wasmuth JJ. Another mutation that results in the substitution of an unpaired cysteine residue in the extracellular domain of FGFR3 in thanatophoric dysplasia type I. Hum Mol Genet. 1995 Nov;4(11):2175-7. PMID:8589699
  13. ↑ Tavormina PL, Shiang R, Thompson LM, Zhu YZ, Wilkin DJ, Lachman RS, Wilcox WR, Rimoin DL, Cohn DH, Wasmuth JJ. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet. 1995 Mar;9(3):321-8. PMID:7773297 doi:http://dx.doi.org/10.1038/ng0395-321
  14. ↑ Rousseau F, el Ghouzzi V, Delezoide AL, Legeai-Mallet L, Le Merrer M, Munnich A, Bonaventure J. Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). Hum Mol Genet. 1996 Apr;5(4):509-12. PMID:8845844
  15. ↑ Katsumata N, Kuno T, Miyazaki S, Mikami S, Nagashima-Miyokawa A, Nimura A, Horikawa R, Tanaka T. G370C mutation in the FGFR3 gene in a Japanese patient with thanatophoric dysplasia. Endocr J. 1998 Apr;45 Suppl:S171-4. PMID:9790257
  16. ↑ Kitoh H, Brodie SG, Kupke KG, Lachman RS, Wilcox WR. Lys650Met substitution in the tyrosine kinase domain of the fibroblast growth factor receptor gene causes thanatophoric dysplasia Type I. Mutations in brief no. 199. Online. Hum Mutat. 1998;12(5):362-3. PMID:10671061
  17. ↑ Brodie SG, Kitoh H, Lachman RS, Nolasco LM, Mekikian PB, Wilcox WR. Platyspondylic lethal skeletal dysplasia, San Diego type, is caused by FGFR3 mutations. Am J Med Genet. 1999 Jun 11;84(5):476-80. PMID:10360402
  18. ↑ Rohmann E, Brunner HG, Kayserili H, Uyguner O, Nurnberg G, Lew ED, Dobbie A, Eswarakumar VP, Uzumcu A, Ulubil-Emeroglu M, Leroy JG, Li Y, Becker C, Lehnerdt K, Cremers CW, Yuksel-Apak M, Nurnberg P, Kubisch C, Schlessinger J, van Bokhoven H, Wollnik B. Mutations in different components of FGF signaling in LADD syndrome. Nat Genet. 2006 Apr;38(4):414-7. Epub 2006 Feb 26. PMID:16501574 doi:ng1757
  19. ↑ Hafner C, van Oers JM, Vogt T, Landthaler M, Stoehr R, Blaszyk H, Hofstaedter F, Zwarthoff EC, Hartmann A. Mosaicism of activating FGFR3 mutations in human skin causes epidermal nevi. J Clin Invest. 2006 Aug;116(8):2201-2207. PMID:16841094 doi:10.1172/JCI28163
  20. ↑ Muenke M, Gripp KW, McDonald-McGinn DM, Gaudenz K, Whitaker LA, Bartlett SP, Markowitz RI, Robin NH, Nwokoro N, Mulvihill JJ, Losken HW, Mulliken JB, Guttmacher AE, Wilroy RS, Clarke LA, Hollway G, Ades LC, Haan EA, Mulley JC, Cohen MM Jr, Bellus GA, Francomano CA, Moloney DM, Wall SA, Wilkie AO, et al.. A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. Am J Hum Genet. 1997 Mar;60(3):555-64. PMID:9042914
  21. ↑ Lajeunie E, El Ghouzzi V, Le Merrer M, Munnich A, Bonaventure J, Renier D. Sex related expressivity of the phenotype in coronal craniosynostosis caused by the recurrent P250R FGFR3 mutation. J Med Genet. 1999 Jan;36(1):9-13. PMID:9950359
  22. ↑ Lowry RB, Jabs EW, Graham GE, Gerritsen J, Fleming J. Syndrome of coronal craniosynostosis, Klippel-Feil anomaly, and sprengel shoulder with and without Pro250Arg mutation in the FGFR3 gene. Am J Med Genet. 2001 Nov 22;104(2):112-9. PMID:11746040
  23. ↑ Logie A, Dunois-Larde C, Rosty C, Levrel O, Blanche M, Ribeiro A, Gasc JM, Jorcano J, Werner S, Sastre-Garau X, Thiery JP, Radvanyi F. Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans. Hum Mol Genet. 2005 May 1;14(9):1153-60. Epub 2005 Mar 16. PMID:15772091 doi:ddi127
  24. ↑ Goriely A, Hansen RM, Taylor IB, Olesen IA, Jacobsen GK, McGowan SJ, Pfeifer SP, McVean GA, Rajpert-De Meyts E, Wilkie AO. Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nat Genet. 2009 Nov;41(11):1247-52. doi: 10.1038/ng.470. Epub 2009 Oct 25. PMID:19855393 doi:10.1038/ng.470
  25. ↑ Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M. Receptor specificity of the fibroblast growth factor family. J Biol Chem. 1996 Jun 21;271(25):15292-7. PMID:8663044
  26. ↑ Monsonego-Ornan E, Adar R, Feferman T, Segev O, Yayon A. The transmembrane mutation G380R in fibroblast growth factor receptor 3 uncouples ligand-mediated receptor activation from down-regulation. Mol Cell Biol. 2000 Jan;20(2):516-22. PMID:10611230
  27. ↑ Hart KC, Robertson SC, Donoghue DJ. Identification of tyrosine residues in constitutively activated fibroblast growth factor receptor 3 involved in mitogenesis, Stat activation, and phosphatidylinositol 3-kinase activation. Mol Biol Cell. 2001 Apr;12(4):931-42. PMID:11294897
  28. ↑ Agazie YM, Movilla N, Ischenko I, Hayman MJ. The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3. Oncogene. 2003 Oct 9;22(44):6909-18. PMID:14534538 doi:10.1038/sj.onc.1206798
  29. ↑ Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem. 2006 Jun 9;281(23):15694-700. Epub 2006 Apr 4. PMID:16597617 doi:10.1074/jbc.M601252200
  30. ↑ Ben-Zvi T, Yayon A, Gertler A, Monsonego-Ornan E. Suppressors of cytokine signaling (SOCS) 1 and SOCS3 interact with and modulate fibroblast growth factor receptor signaling. J Cell Sci. 2006 Jan 15;119(Pt 2):380-7. PMID:16410555 doi:10.1242/jcs.02740
  31. ↑ Harada D, Yamanaka Y, Ueda K, Nishimura R, Morishima T, Seino Y, Tanaka H. Sustained phosphorylation of mutated FGFR3 is a crucial feature of genetic dwarfism and induces apoptosis in the ATDC5 chondrogenic cell line via PLCgamma-activated STAT1. Bone. 2007 Aug;41(2):273-81. Epub 2007 Feb 9. PMID:17561467 doi:10.1016/j.bone.2006.11.030
  32. ↑ Bonaventure J, Horne WC, Baron R. The localization of FGFR3 mutations causing thanatophoric dysplasia type I differentially affects phosphorylation, processing and ubiquitylation of the receptor. FEBS J. 2007 Jun;274(12):3078-93. Epub 2007 May 17. PMID:17509076 doi:10.1111/j.1742-4658.2007.05835.x
  33. ↑ Krejci P, Masri B, Salazar L, Farrington-Rock C, Prats H, Thompson LM, Wilcox WR. Bisindolylmaleimide I suppresses fibroblast growth factor-mediated activation of Erk MAP kinase in chondrocytes by preventing Shp2 association with the Frs2 and Gab1 adaptor proteins. J Biol Chem. 2007 Feb 2;282(5):2929-36. Epub 2006 Dec 4. PMID:17145761 doi:10.1074/jbc.M606144200
  34. ↑ Citores L, Bai L, Sorensen V, Olsnes S. Fibroblast growth factor receptor-induced phosphorylation of STAT1 at the Golgi apparatus without translocation to the nucleus. J Cell Physiol. 2007 Jul;212(1):148-56. PMID:17311277 doi:10.1002/jcp.21014
  35. ↑ Krejci P, Salazar L, Kashiwada TA, Chlebova K, Salasova A, Thompson LM, Bryja V, Kozubik A, Wilcox WR. Analysis of STAT1 activation by six FGFR3 mutants associated with skeletal dysplasia undermines dominant role of STAT1 in FGFR3 signaling in cartilage. PLoS One. 2008;3(12):e3961. doi: 10.1371/journal.pone.0003961. Epub 2008 Dec 17. PMID:19088846 doi:10.1371/journal.pone.0003961
  36. ↑ Salazar L, Kashiwada T, Krejci P, Muchowski P, Donoghue D, Wilcox WR, Thompson LM. A novel interaction between fibroblast growth factor receptor 3 and the p85 subunit of phosphoinositide 3-kinase: activation-dependent regulation of ERK by p85 in multiple myeloma cells. Hum Mol Genet. 2009 Jun 1;18(11):1951-61. doi: 10.1093/hmg/ddp116. Epub 2009 Mar , 13. PMID:19286672 doi:10.1093/hmg/ddp116
  37. ↑ Kuriwaki I, Kameda M, Hisamichi H, Kikuchi S, Iikubo K, Kawamoto Y, Moritomo H, Kondoh Y, Amano Y, Tateishi Y, Echizen Y, Iwai Y, Noda A, Tomiyama H, Suzuki T, Hirano M. Structure-based drug design of 1,3,5-triazine and pyrimidine derivatives as novel FGFR3 inhibitors with high selectivity over VEGFR2. Bioorg Med Chem. 2020 May 15;28(10):115453. doi: 10.1016/j.bmc.2020.115453. Epub , 2020 Mar 28. PMID:32278710 doi:http://dx.doi.org/10.1016/j.bmc.2020.115453

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PDB ID 6lvm

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