| Structural highlights
3t3m is a 8 chain structure with sequence from Human and Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | BMA, CA, CL, NAG, RC2, SO4, MAN |
| Related: | 3nid, 3nif, 3nig |
| Gene: | ITGA2B, GP2B, ITGAB (HUMAN), ITGB3, GP3A (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[ITA2B_HUMAN] Defects in ITGA2B are a cause of Glanzmann thrombasthenia (GT) [MIM:273800]; also known as thrombasthenia of Glanzmann and Naegeli. GT is the most common inherited disease of platelets. It is an autosomal recessive disorder characterized by mucocutaneous bleeding of mild-to-moderate severity and the inability of this integrin to recognize macromolecular or synthetic peptide ligands. GT has been classified clinically into types I and II. In type I, platelets show absence of the glycoprotein IIb/beta-3 complexes at their surface and lack fibrinogen and clot retraction capability. In type II, the platelets express the glycoprotein IIb/beta-3 complex at reduced levels (5-20% controls), have detectable amounts of fibrinogen, and have low or moderate clot retraction capability. The platelets of GT 'variants' have normal or near normal (60-100%) expression of dysfunctional receptors.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [ITB3_HUMAN] Defects in ITGB3 are a cause of Glanzmann thrombasthenia (GT) [MIM:273800]; also known as thrombasthenia of Glanzmann and Naegeli. GT is the most common inherited disease of platelets. It is an autosomal recessive disorder characterized by mucocutaneous bleeding of mild-to-moderate severity and the inability of this integrin to recognize macromolecular or synthetic peptide ligands. GT has been classified clinically into types I and II. In type I, platelets show absence of the glycoprotein IIb/beta-3 complexes at their surface and lack fibrinogen and clot retraction capability. In type II, the platelets express the glycoprotein IIb/beta-3 complex at reduced levels (5-20% controls), have detectable amounts of fibrinogen, and have low or moderate clot retraction capability. The platelets of GT 'variants' have normal or near normal (60-100%) expression of dysfunctional receptors.[20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36]
Function
[ITA2B_HUMAN] Integrin alpha-IIb/beta-3 is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. It recognizes the sequence R-G-D in a wide array of ligands. It recognizes the sequence H-H-L-G-G-G-A-K-Q-A-G-D-V in fibrinogen gamma chain. Following activation integrin alpha-IIb/beta-3 brings about platelet/platelet interaction through binding of soluble fibrinogen. This step leads to rapid platelet aggregation which physically plugs ruptured endothelial cell surface. [ITB3_HUMAN] Integrin alpha-V/beta-3 is a receptor for cytotactin, fibronectin, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin, vitronectin and von Willebrand factor. Integrin alpha-IIb/beta-3 is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. Integrins alpha-IIb/beta-3 and alpha-V/beta-3 recognize the sequence R-G-D in a wide array of ligands. Integrin alpha-IIb/beta-3 recognizes the sequence H-H-L-G-G-G-A-K-Q-A-G-D-V in fibrinogen gamma chain. Following activation integrin alpha-IIb/beta-3 brings about platelet/platelet interaction through binding of soluble fibrinogen. This step leads to rapid platelet aggregation which physically plugs ruptured endothelial surface. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.
Publication Abstract from PubMed
An integrin found on platelets, alpha(IIb)beta(3) mediates platelet aggregation, and alpha(IIb)beta(3) antagonists are effective antithrombotic agents in the clinic. Ligands bind to integrins in part by coordinating a magnesium ion (Mg(2+)) located in the beta subunit metal ion-dependent adhesion site (MIDAS). Drugs patterned on the integrin ligand sequence Arg-Gly-Asp have a basic moiety that binds the alpha(IIb) subunit and a carboxyl group that coordinates the MIDAS Mg(2+) in the beta(3) subunits. They induce conformational changes in the beta(3) subunit that may have negative consequences such as exposing previously hidden epitopes and inducing the active conformation of the receptor. We recently reported an inhibitor of alpha(IIb)beta(3) (RUC-1) that binds exclusively to the alpha(IIb) subunit; here, we report the structure-based design and synthesis of RUC-2, a RUC-1 derivative with a ~100-fold higher affinity. RUC-2 does not induce major conformational changes in beta(3) as judged by monoclonal antibody binding, light scattering, gel chromatography, electron microscopy, and a receptor priming assay. X-ray crystallography of the RUC-2-alpha(IIb)beta(3) headpiece complex in 1 mM calcium ion (Ca(2+))/5 mM Mg(2+) at 2.6 A revealed that RUC-2 binds to alpha(IIb) the way RUC-1 does, but in addition, it binds to the beta(3) MIDAS residue glutamic acid 220, thus displacing Mg(2+) from the MIDAS. When the Mg(2+) concentration was increased to 20 mM, however, Mg(2+) was identified in the MIDAS and RUC-2 was absent. RUC-2's ability to inhibit ligand binding and platelet aggregation was diminished by increasing the Mg(2+) concentration. Thus, RUC-2 inhibits ligand binding by a mechanism different from that of all other alpha(IIb)beta(3) antagonists and may offer advantages as a therapeutic agent.
Structure-Guided Design of a High-Affinity Platelet Integrin alphaIIbbeta3 Receptor Antagonist That Disrupts Mg2+ Binding to the MIDAS.,Zhu J, Choi WS, McCoy JG, Negri A, Zhu J, Naini S, Li J, Shen M, Huang W, Bougie D, Rasmussen M, Aster R, Thomas CJ, Filizola M, Springer TA, Coller BS Sci Transl Med. 2012 Mar 14;4(125):125ra32. PMID:22422993[37]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Poncz M, Rifat S, Coller BS, Newman PJ, Shattil SJ, Parrella T, Fortina P, Bennett JS. Glanzmann thrombasthenia secondary to a Gly273-->Asp mutation adjacent to the first calcium-binding domain of platelet glycoprotein IIb. J Clin Invest. 1994 Jan;93(1):172-9. PMID:8282784 doi:https://dx.doi.org/10.1172/JCI116942
- ↑ Wilcox DA, Wautier JL, Pidard D, Newman PJ. A single amino acid substitution flanking the fourth calcium binding domain of alpha IIb prevents maturation of the alpha IIb beta 3 integrin complex. J Biol Chem. 1994 Feb 11;269(6):4450-7. PMID:7508443
- ↑ Wilcox DA, Paddock CM, Lyman S, Gill JC, Newman PJ. Glanzmann thrombasthenia resulting from a single amino acid substitution between the second and third calcium-binding domains of GPIIb. Role of the GPIIb amino terminus in integrin subunit association. J Clin Invest. 1995 Apr;95(4):1553-60. PMID:7706461 doi:https://dx.doi.org/10.1172/JCI117828
- ↑ Basani RB, Vilaire G, Shattil SJ, Kolodziej MA, Bennett JS, Poncz M. Glanzmann thrombasthenia due to a two amino acid deletion in the fourth calcium-binding domain of alpha IIb: demonstration of the importance of calcium-binding domains in the conformation of alpha IIb beta 3. Blood. 1996 Jul 1;88(1):167-73. PMID:8704171
- ↑ French DL, Coller BS. Hematologically important mutations: Glanzmann thrombasthenia. Blood Cells Mol Dis. 1997;23(1):39-51. PMID:9215749 doi:10.1006/bcmd.1997.0117
- ↑ Grimaldi CM, Chen F, Wu C, Weiss HJ, Coller BS, French DL. Glycoprotein IIb Leu214Pro mutation produces glanzmann thrombasthenia with both quantitative and qualitative abnormalities in GPIIb/IIIa. Blood. 1998 Mar 1;91(5):1562-71. PMID:9473221
- ↑ Tadokoro S, Tomiyama Y, Honda S, Arai M, Yamamoto N, Shiraga M, Kosugi S, Kanakura Y, Kurata Y, Matsuzawa Y. A Gln747-->Pro substitution in the IIb subunit is responsible for a moderate IIbbeta3 deficiency in Glanzmann thrombasthenia. Blood. 1998 Oct 15;92(8):2750-8. PMID:9763559
- ↑ Ambo H, Kamata T, Handa M, Kawai Y, Oda A, Murata M, Takada Y, Ikeda Y. Novel point mutations in the alphaIIb subunit (Phe289-->Ser, Glu324-->Lys and Gln747-->Pro) causing thrombasthenic phenotypes in four Japanese patients. Br J Haematol. 1998 Aug;102(3):829-40. PMID:9722314
- ↑ Ruan J, Peyruchaud O, Alberio L, Valles G, Clemetson K, Bourre F, Nurden AT. Double heterozygosity of the GPIIb gene in a Swiss patient with Glanzmann's thrombasthenia. Br J Haematol. 1998 Sep;102(4):918-25. PMID:9734640
- ↑ Gonzalez-Manchon C, Fernandez-Pinel M, Arias-Salgado EG, Ferrer M, Alvarez MV, Garcia-Munoz S, Ayuso MS, Parrilla R. Molecular genetic analysis of a compound heterozygote for the glycoprotein (GP) IIb gene associated with Glanzmann's thrombasthenia: disruption of the 674-687 disulfide bridge in GPIIb prevents surface exposure of GPIIb-IIIa complexes. Blood. 1999 Feb 1;93(3):866-75. PMID:9920835
- ↑ Basani RB, French DL, Vilaire G, Brown DL, Chen F, Coller BS, Derrick JM, Gartner TK, Bennett JS, Poncz M. A naturally occurring mutation near the amino terminus of alphaIIb defines a new region involved in ligand binding to alphaIIbbeta3. Blood. 2000 Jan 1;95(1):180-8. PMID:10607701
- ↑ Vinciguerra C, Bordet JC, Beaune G, Grenier C, Dechavanne M, Negrier C. Description of 10 new mutations in platelet glycoprotein IIb (alphaIIb) and glycoprotein IIIa (beta3) genes. Platelets. 2001 Dec;12(8):486-95. PMID:11798398 doi:10.1080/095371001317126383
- ↑ Tanaka S, Hayashi T, Hori Y, Terada C, Han KS, Ahn HS, Bourre F, Tani Y. A Leu55 to Pro substitution in the integrin alphaIIb is responsible for a case of Glanzmann's thrombasthenia. Br J Haematol. 2002 Sep;118(3):833-5. PMID:12181054
- ↑ D'Andrea G, Colaizzo D, Vecchione G, Grandone E, Di Minno G, Margaglione M. Glanzmann's thrombasthenia: identification of 19 new mutations in 30 patients. Thromb Haemost. 2002 Jun;87(6):1034-42. PMID:12083483
- ↑ Mitchell WB, Li JH, Singh F, Michelson AD, Bussel J, Coller BS, French DL. Two novel mutations in the alpha IIb calcium-binding domains identify hydrophobic regions essential for alpha IIbbeta 3 biogenesis. Blood. 2003 Mar 15;101(6):2268-76. Epub 2002 Nov 7. PMID:12424194 doi:10.1182/blood-2002-07-2266
- ↑ Kiyoi T, Tomiyama Y, Honda S, Tadokoro S, Arai M, Kashiwagi H, Kosugi S, Kato H, Kurata Y, Matsuzawa Y. A naturally occurring Tyr143His alpha IIb mutation abolishes alpha IIb beta 3 function for soluble ligands but retains its ability for mediating cell adhesion and clot retraction: comparison with other mutations causing ligand-binding defects. Blood. 2003 May 1;101(9):3485-91. Epub 2002 Dec 27. PMID:12506038 doi:10.1182/blood-2002-07-2144
- ↑ Nurden AT, Breillat C, Jacquelin B, Combrie R, Freedman J, Blanchette VS, Schmugge M, Rand ML. Triple heterozygosity in the integrin alphaIIb subunit in a patient with Glanzmann's thrombasthenia. J Thromb Haemost. 2004 May;2(5):813-9. PMID:15099289 doi:10.1046/j.1538-7836.2004.00711.x
- ↑ Rosenberg N, Landau M, Luboshitz J, Rechavi G, Seligsohn U. A novel Phe171Cys mutation in integrin alpha causes Glanzmann thrombasthenia by abrogating alphabeta complex formation. J Thromb Haemost. 2004 Jul;2(7):1167-75. PMID:15219201 doi:10.1111/j.1538-7836.2004.00758.x
- ↑ Jayo A, Pabon D, Lastres P, Jimenez-Yuste V, Gonzalez-Manchon C. Type II Glanzmann thrombasthenia in a compound heterozygote for the alpha IIb gene. A novel missense mutation in exon 27. Haematologica. 2006 Oct;91(10):1352-9. PMID:17018384
- ↑ Loftus JC, O'Toole TE, Plow EF, Glass A, Frelinger AL 3rd, Ginsberg MH. A beta 3 integrin mutation abolishes ligand binding and alters divalent cation-dependent conformation. Science. 1990 Aug 24;249(4971):915-8. PMID:2392682
- ↑ Bajt ML, Ginsberg MH, Frelinger AL 3rd, Berndt MC, Loftus JC. A spontaneous mutation of integrin alpha IIb beta 3 (platelet glycoprotein IIb-IIIa) helps define a ligand binding site. J Biol Chem. 1992 Feb 25;267(6):3789-94. PMID:1371279
- ↑ Lanza F, Stierle A, Fournier D, Morales M, Andre G, Nurden AT, Cazenave JP. A new variant of Glanzmann's thrombasthenia (Strasbourg I). Platelets with functionally defective glycoprotein IIb-IIIa complexes and a glycoprotein IIIa 214Arg----214Trp mutation. J Clin Invest. 1992 Jun;89(6):1995-2004. PMID:1602006 doi:https://dx.doi.org/10.1172/JCI115808
- ↑ Chen YP, Djaffar I, Pidard D, Steiner B, Cieutat AM, Caen JP, Rosa JP. Ser-752-->Pro mutation in the cytoplasmic domain of integrin beta 3 subunit and defective activation of platelet integrin alpha IIb beta 3 (glycoprotein IIb-IIIa) in a variant of Glanzmann thrombasthenia. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10169-73. PMID:1438206
- ↑ Grimaldi CM, Chen F, Scudder LE, Coller BS, French DL. A Cys374Tyr homozygous mutation of platelet glycoprotein IIIa (beta 3) in a Chinese patient with Glanzmann's thrombasthenia. Blood. 1996 Sep 1;88(5):1666-75. PMID:8781422
- ↑ Basani RB, Brown DL, Vilaire G, Bennett JS, Poncz M. A Leu117-->Trp mutation within the RGD-peptide cross-linking region of beta3 results in Glanzmann thrombasthenia by preventing alphaIIb beta3 export to the platelet surface. Blood. 1997 Oct 15;90(8):3082-8. PMID:9376589
- ↑ French DL, Coller BS. Hematologically important mutations: Glanzmann thrombasthenia. Blood Cells Mol Dis. 1997;23(1):39-51. PMID:9215749 doi:10.1006/bcmd.1997.0117
- ↑ Ambo H, Kamata T, Handa M, Taki M, Kuwajima M, Kawai Y, Oda A, Murata M, Takada Y, Watanabe K, Ikeda Y. Three novel integrin beta3 subunit missense mutations (H280P, C560F, and G579S) in thrombasthenia, including one (H280P) prevalent in Japanese patients. Biochem Biophys Res Commun. 1998 Oct 29;251(3):763-8. PMID:9790984 doi:10.1006/bbrc.1998.9526
- ↑ Jackson DE, White MM, Jennings LK, Newman PJ. A Ser162-->Leu mutation within glycoprotein (GP) IIIa (integrin beta3) results in an unstable alphaIIbbeta3 complex that retains partial function in a novel form of type II Glanzmann thrombasthenia. Thromb Haemost. 1998 Jul;80(1):42-8. PMID:9684783
- ↑ Ruan J, Schmugge M, Clemetson KJ, Cazes E, Combrie R, Bourre F, Nurden AT. Homozygous Cys542-->Arg substitution in GPIIIa in a Swiss patient with type I Glanzmann's thrombasthenia. Br J Haematol. 1999 May;105(2):523-31. PMID:10233432
- ↑ Ruiz C, Liu CY, Sun QH, Sigaud-Fiks M, Fressinaud E, Muller JY, Nurden P, Nurden AT, Newman PJ, Valentin N. A point mutation in the cysteine-rich domain of glycoprotein (GP) IIIa results in the expression of a GPIIb-IIIa (alphaIIbbeta3) integrin receptor locked in a high-affinity state and a Glanzmann thrombasthenia-like phenotype. Blood. 2001 Oct 15;98(8):2432-41. PMID:11588040
- ↑ Nurden AT, Ruan J, Pasquet JM, Gauthier B, Combrie R, Kunicki T, Nurden P. A novel 196Leu to Pro substitution in the beta3 subunit of the alphaIIbbeta3 integrin in a patient with a variant form of Glanzmann thrombasthenia. Platelets. 2002 Mar;13(2):101-11. PMID:11897046 doi:10.1080/09537100220122466
- ↑ D'Andrea G, Colaizzo D, Vecchione G, Grandone E, Di Minno G, Margaglione M. Glanzmann's thrombasthenia: identification of 19 new mutations in 30 patients. Thromb Haemost. 2002 Jun;87(6):1034-42. PMID:12083483
- ↑ Nair S, Li J, Mitchell WB, Mohanty D, Coller BS, French DL. Two new beta3 integrin mutations in Indian patients with Glanzmann thrombasthenia: localization of mutations affecting cysteine residues in integrin beta3. Thromb Haemost. 2002 Sep;88(3):503-9. PMID:12353082 doi:10.1267/THRO88030503
- ↑ Gonzalez-Manchon C, Butta N, Larrucea S, Arias-Salgado EG, Alonso S, Lopez A, Parrilla R. A variant thrombasthenic phenotype associated with compound heterozygosity of integrin beta3-subunit: (Met124Val)beta3 alters the subunit dimerization rendering a decreased number of constitutive active alphaIIbbeta3 receptors. Thromb Haemost. 2004 Dec;92(6):1377-86. PMID:15583747 doi:04121377
- ↑ Tanaka S, Hayashi T, Yoshimura K, Nakayama M, Fujita T, Amano T, Tani Y. Double heterozygosity for a novel missense mutation of Ile304 to Asn in addition to the missense mutation His280 to Pro in the integrin beta3 gene as a cause of the absence of platelet alphaIIbbeta3 in Glanzmann's thrombasthenia. J Thromb Haemost. 2005 Jan;3(1):68-73. PMID:15634267 doi:JTH990
- ↑ Nair S, Ghosh K, Shetty S, Mohanty D. Mutations in GPIIIa molecule as a cause for Glanzmann thrombasthenia in Indian patients. J Thromb Haemost. 2005 Mar;3(3):482-8. PMID:15748237 doi:JTH1159
- ↑ Zhu J, Choi WS, McCoy JG, Negri A, Zhu J, Naini S, Li J, Shen M, Huang W, Bougie D, Rasmussen M, Aster R, Thomas CJ, Filizola M, Springer TA, Coller BS. Structure-Guided Design of a High-Affinity Platelet Integrin alphaIIbbeta3 Receptor Antagonist That Disrupts Mg2+ Binding to the MIDAS. Sci Transl Med. 2012 Mar 14;4(125):125ra32. PMID:22422993 doi:10.1126/scitranslmed.3003576
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