8r8d

From Proteopedia

(Difference between revisions)

Current revision

Cryo-EM structure of coagulation factor beta-XIIa in complex with the garadacimab Fab fragment (symmetric dimer)

Structural highlights

8r8d is a 6 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:	Electron Microscopy, Resolution 2.6Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

FA12_HUMAN Congenital factor XII deficiency;Hereditary angioedema type 3. Defects in F12 are the cause of factor XII deficiency (FA12D) [MIM:234000; also known as Hageman factor deficiency. This trait is an asymptomatic anomaly of in vitro blood coagulation. Its diagnosis is based on finding a low plasma activity of the factor in coagulating assays. It is usually only accidentally discovered through pre-operative blood tests. F12 deficiency is divided into two categories, a cross-reacting material (CRM)-negative group (negative F12 antigen detection) and a CRM-positive group (positive F12 antigen detection).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] Defects in F12 are the cause of hereditary angioedema type 3 (HAE3) [MIM:610618; also known as estrogen-related HAE or hereditary angioneurotic edema with normal C1 inhibitor concentration and function. HAE is characterized by episodic local subcutaneous edema, and submucosal edema involving the upper respiratory and gastrointestinal tracts. HAE3 occurs exclusively in women and is precipitated or worsened by high estrogen levels (e.g. during pregnancy or treatment with oral contraceptives). It differs from HAE types 1 and 2 in that both concentration and function of C1 inhibitor are normal.^[10] ^[11]

Function

FA12_HUMAN Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then trypsin cleaves it to beta-factor XIIa. Alpha-factor XIIa activates factor XI to factor XIa.^[12]

Publication Abstract from PubMed

Activated FXII (FXIIa) is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of hereditary angioedema (HAE). Here, we describe a high-resolution cryoelectron microscopy (cryo-EM) structure of the beta-chain from FXIIa (betaFXIIa) complexed with the Fab fragment of garadacimab. Garadacimab binds to betaFXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This structural mechanism is likely the primary contributor to the inhibition of activated FXIIa proteolytic activity in HAE. Garadacimab Fab-betaFXIIa structure also reveals critical determinants of high-affinity binding of garadacimab to activated FXIIa. Structural analysis with other bona fide FXIIa inhibitors, such as benzamidine and C1-INH, reveals a surprisingly similar mechanism of betaFXIIa inhibition by garadacimab. In summary, the garadacimab Fab-betaFXIIa structure provides crucial insights into its mechanism of action and delineates primary and auxiliary paratopes/epitopes.

Structural basis for the inhibition of betaFXIIa by garadacimab.,Drulyte I, Ghai R, Ow SY, Kapp EA, Quek AJ, Panousis C, Wilson MJ, Nash AD, Pelzing M Structure. 2024 Jul 13:S0969-2126(24)00239-9. doi: 10.1016/j.str.2024.07.001. PMID:39059382^[13]

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

References

↑ Schloesser M, Hofferbert S, Bartz U, Lutze G, Lammle B, Engel W. The novel acceptor splice site mutation 11396(G-->A) in the factor XII gene causes a truncated transcript in cross-reacting material negative patients. Hum Mol Genet. 1995 Jul;4(7):1235-7. PMID:8528215
↑ Bernardi F, Marchetti G, Patracchini P, del Senno L, Tripodi M, Fantoni A, Bartolai S, Vannini F, Felloni L, Rossi L, et al.. Factor XII gene alteration in Hageman trait detected by TaqI restriction enzyme. Blood. 1987 May;69(5):1421-4. PMID:2882793
↑ Miyata T, Kawabata S, Iwanaga S, Takahashi I, Alving B, Saito H. Coagulation factor XII (Hageman factor) Washington D.C.: inactive factor XIIa results from Cys-571----Ser substitution. Proc Natl Acad Sci U S A. 1989 Nov;86(21):8319-22. PMID:2510163
↑ Hovinga JK, Schaller J, Stricker H, Wuillemin WA, Furlan M, Lammle B. Coagulation factor XII Locarno: the functional defect is caused by the amino acid substitution Arg 353-->Pro leading to loss of a kallikrein cleavage site. Blood. 1994 Aug 15;84(4):1173-81. PMID:8049433
↑ Schloesser M, Zeerleder S, Lutze G, Halbmayer WM, Hofferbert S, Hinney B, Koestering H, Lammle B, Pindur G, Thies K, Kohler M, Engel W. Mutations in the human factor XII gene. Blood. 1997 Nov 15;90(10):3967-77. PMID:9354665
↑ Kondo S, Tokunaga F, Kawano S, Oono Y, Kumagai S, Koide T. Factor XII Tenri, a novel cross-reacting material negative factor XII deficiency, occurs through a proteasome-mediated degradation. Blood. 1999 Jun 15;93(12):4300-8. PMID:10361128
↑ Kanaji T, Kanaji S, Osaki K, Kuroiwa M, Sakaguchi M, Mihara K, Niho Y, Okamura T. Identification and characterization of two novel mutations (Q421 K and R123P) in congenital factor XII deficiency. Thromb Haemost. 2001 Dec;86(6):1409-15. PMID:11776307
↑ Ishii K, Oguchi S, Moriki T, Yatabe Y, Takeshita E, Murata M, Ikeda Y, Watanabe K. Genetic analyses and expression studies identified a novel mutation (W486C) as a molecular basis of congenital coagulation factor XII deficiency. Blood Coagul Fibrinolysis. 2004 Jul;15(5):367-73. PMID:15205584
↑ Oguchi S, Ishii K, Moriki T, Takeshita E, Murata M, Ikeda Y, Watanabe K. Factor XII Shizuoka, a novel mutation (Ala392Thr) identified and characterized in a patient with congenital coagulation factor XII deficiency. Thromb Res. 2005;115(3):191-7. PMID:15617741 doi:10.1016/j.thromres.2004.08.027
↑ Dewald G, Bork K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun. 2006 May 19;343(4):1286-9. PMID:16638441 doi:S0006-291X(06)00611-5
↑ Cichon S, Martin L, Hennies HC, Muller F, Van Driessche K, Karpushova A, Stevens W, Colombo R, Renne T, Drouet C, Bork K, Nothen MM. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet. 2006 Dec;79(6):1098-104. Epub 2006 Oct 18. PMID:17186468 doi:S0002-9297(07)63472-7
↑ MacQuarrie JL, Stafford AR, Yau JW, Leslie BA, Vu TT, Fredenburgh JC, Weitz JI. Histidine-rich glycoprotein binds factor XIIa with high affinity and inhibits contact-initiated coagulation. Blood. 2011 Apr 14;117(15):4134-41. doi: 10.1182/blood-2010-07-290551. Epub 2011 , Feb 8. PMID:21304106 doi:10.1182/blood-2010-07-290551
↑ Drulyte I, Ghai R, Ow SY, Kapp EA, Quek AJ, Panousis C, Wilson MJ, Nash AD, Pelzing M. Structural basis for the inhibition of βFXIIa by garadacimab. Structure. 2024 Jul 13:S0969-2126(24)00239-9. PMID:39059382 doi:10.1016/j.str.2024.07.001

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8r8d"

Categories: Homo sapiens | Large Structures | Drulyte I

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[8r8d]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8R8D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8R8D FirstGlance]. <br>
 </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.6&#8491;</td></tr>
-<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8r8d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8r8d OCA], [https://pdbe.org/8r8d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8r8d RCSB], [https://www.ebi.ac.uk/pdbsum/8r8d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8r8d ProSAT]</span></td></tr>
 </table>
@@ Line 12: / Line 11: @@
 == Function ==
 [https://www.uniprot.org/uniprot/FA12_HUMAN FA12_HUMAN] Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then trypsin cleaves it to beta-factor XIIa. Alpha-factor XIIa activates factor XI to factor XIa.<ref>PMID:21304106</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Activated FXII (FXIIa) is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of hereditary angioedema (HAE). Here, we describe a high-resolution cryoelectron microscopy (cryo-EM) structure of the beta-chain from FXIIa (betaFXIIa) complexed with the Fab fragment of garadacimab. Garadacimab binds to betaFXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This structural mechanism is likely the primary contributor to the inhibition of activated FXIIa proteolytic activity in HAE. Garadacimab Fab-betaFXIIa structure also reveals critical determinants of high-affinity binding of garadacimab to activated FXIIa. Structural analysis with other bona fide FXIIa inhibitors, such as benzamidine and C1-INH, reveals a surprisingly similar mechanism of betaFXIIa inhibition by garadacimab. In summary, the garadacimab Fab-betaFXIIa structure provides crucial insights into its mechanism of action and delineates primary and auxiliary paratopes/epitopes.
+Structural basis for the inhibition of betaFXIIa by garadacimab.,Drulyte I, Ghai R, Ow SY, Kapp EA, Quek AJ, Panousis C, Wilson MJ, Nash AD, Pelzing M Structure. 2024 Jul 13:S0969-2126(24)00239-9. doi: 10.1016/j.str.2024.07.001. PMID:39059382<ref>PMID:39059382</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 8r8d" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

8r8d

From Proteopedia

Current revision

Cryo-EM structure of coagulation factor beta-XIIa in complex with the garadacimab Fab fragment (symmetric dimer)

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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