6r8x - Revision history

OCA at 07:37, 1 May 2024

2024-05-01T07:37:26Z

←Older revision		Revision as of 07:37, 1 May 2024
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	<StructureSection load='6r8x' size='340' side='right'caption='[[6r8x]], [[Resolution\|resolution]] 2.04Å' scene=''>		<StructureSection load='6r8x' size='340' side='right'caption='[[6r8x]], [[Resolution\|resolution]] 2.04Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6r8x]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R8X OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6R8X FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6r8x]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Unidentified Unidentified]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R8X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6R8X FirstGlance]. <br>
-	</td></tr><tr id='~~activity~~'><td class="sblockLbl"><b>~~Activity~~:</b></td><td class="sblockDat"~~><span class~~=~~'plainlinks'~~>[~~http://en.wikipedia.org/wiki/Coagulation_factor_XIa Coagulation factor XIa~~]~~, with EC number [http://www~~.~~brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.27 3.4.21.27] </span>~~</td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.04Å</td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6r8x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r8x OCA], [~~http~~://pdbe.org/6r8x PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6r8x RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6r8x PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6r8x ProSAT]</span></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=6r8x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r8x OCA], [https://pdbe.org/6r8x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6r8x RCSB], [https://www.ebi.ac.uk/pdbsum/6r8x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6r8x ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Defects in F11 are the cause of factor XI deficiency (FA11D) [MIM:[~~http~~://omim.org/entry/612416 612416]]; also known as plasma thromboplastin antecedent deficiency or Rosenthal syndrome. It is a hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate.<ref>PMID:2813350</ref> <ref>PMID:1547342</ref> <ref>PMID:7888672</ref> <ref>PMID:7669672</ref> <ref>PMID:9401068</ref> <ref>PMID:9787168</ref> <ref>PMID:10027710</ref> <ref>PMID:10606881</ref> <ref>PMID:11895778</ref> <ref>PMID:15026311</ref> <ref>PMID:15180874</ref> <ref>PMID:15953011</ref> <ref>PMID:16607084</ref> <ref>PMID:18005151</ref> <ref>PMID:21668437</ref> <ref>PMID:21457405</ref> <ref>PMID:22016685</ref> <ref>PMID:22322133</ref> <ref>PMID:21999818</ref> <ref>PMID:22159456</ref>	+	[https://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN] Defects in F11 are the cause of factor XI deficiency (FA11D) [MIM:[https://omim.org/entry/612416 612416]; also known as plasma thromboplastin antecedent deficiency or Rosenthal syndrome. It is a hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate.<ref>PMID:2813350</ref> <ref>PMID:1547342</ref> <ref>PMID:7888672</ref> <ref>PMID:7669672</ref> <ref>PMID:9401068</ref> <ref>PMID:9787168</ref> <ref>PMID:10027710</ref> <ref>PMID:10606881</ref> <ref>PMID:11895778</ref> <ref>PMID:15026311</ref> <ref>PMID:15180874</ref> <ref>PMID:15953011</ref> <ref>PMID:16607084</ref> <ref>PMID:18005151</ref> <ref>PMID:21668437</ref> <ref>PMID:21457405</ref> <ref>PMID:22016685</ref> <ref>PMID:22322133</ref> <ref>PMID:21999818</ref> <ref>PMID:22159456</ref>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX.	+	[https://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN] Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX.
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	A large unmet medical need exists for safer antithrombotic drugs because all currently approved anticoagulant agents interfere with hemostasis, leading to an increased risk of bleeding. Genetic and pharmacologic evidence in humans and animals suggests that reducing factor XI (FXI) levels has the potential to effectively prevent and treat thrombosis with a minimal risk of bleeding. We generated a fully human antibody (MAA868) that binds the catalytic domain of both FXI (zymogen) and activated FXI. Our structural studies show that MAA868 traps FXI and activated FXI in an inactive, zymogen-like conformation, explaining its equally high binding affinity for both forms of the enzyme. This binding mode allows the enzyme to be neutralized before entering the coagulation process, revealing a particularly attractive anticoagulant profile of the antibody. MAA868 exhibited favorable anticoagulant activity in mice with a dose-dependent protection from carotid occlusion in a ferric chloride-induced thrombosis model. MAA868 also caused robust and sustained anticoagulant activity in cynomolgus monkeys as assessed by activated partial thromboplastin time without any evidence of bleeding. Based on these preclinical findings, we conducted a first-in-human study in healthy subjects and showed that single subcutaneous doses of MAA868 were safe and well tolerated. MAA868 resulted in dose- and time-dependent robust and sustained prolongation of activated partial thromboplastin time and FXI suppression for up to 4 weeks or longer, supporting further clinical investigation as a potential once-monthly subcutaneous anticoagulant therapy.	+

-	MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulation in humans.,Koch AW, Schiering N, Melkko S, Ewert S, Salter J, Zhang Y, McCormack P, Yu J, Huang X, Chiu YH, Chen Z, Schleeger S, Horny G, DiPetrillo K, Muller L, Hein A, Villard F, Scharenberg M, Ramage P, Hassiepen U, Cote S, DeGagne J, Krantz C, Eder J, Stoll B, Kulmatycki K, Feldman DL, Hoffmann P, Basson CT, Frost RJA, Khder Y Blood. 2019 Mar 28;133(13):1507-1516. doi: 10.1182/blood-2018-10-880849. Epub, 2019 Jan 28. PMID:30692123<ref>PMID:30692123</ref>	+	==See Also==
-		+	*[[Antibody 3D structures\|Antibody 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+	*[[Factor XIa 3D structures\|Factor XIa 3D structures]]
-	~~</div>~~	+
-	~~<div class~~=~~"pdbe-citations 6r8x" style~~=~~"background-color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Coagulation factor XIa~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Koch, A~~]]	+	[[Category: Unidentified]]
-	[[Category: ~~Schiering, N~~]]	+	[[Category: Koch A]]
-	[[Category: ~~Antagonist]]~~	+	[[Category: Schiering N]]
-	~~[[Category: Antibody]]~~	+
-	~~[[Category: Blood clotting]]~~	+
-	~~[[Category: Coagulation fxi]]~~	+
-	~~[[Category: Zymogen~~]]	+

OCA: Protected "6r8x" [edit=sysop:move=sysop]

2019-04-10T07:32:30Z

Protected "6r8x" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:32, 10 April 2019

OCA: New page: ==COAGULATION FACTOR XI CATALYTIC DOMAIN IN COMPLEX WITH FAB-PORTION OF MAA868== == Structural highlights ==
<table><tr><td colspan='2'>[[6r8x]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R8X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6R8X FirstGlance]. <br>
</td></tr><tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Coagulation_factor_XIa Coagulation factor XIa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.27 3.4.21.27] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6r8x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r8x OCA], [http://pdbe.org/6r8x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6r8x RCSB], [http://www.ebi.ac.uk/pdbsum/6r8x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6r8x ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Defects in F11 are the cause of factor XI deficiency (FA11D) [MIM:[http://omim.org/entry/612416 612416]]; also known as plasma thromboplastin antecedent deficiency or Rosenthal syndrome. It is a hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate.<ref>PMID:2813350</ref> <ref>PMID:1547342</ref> <ref>PMID:7888672</ref> <ref>PMID:7669672</ref> <ref>PMID:9401068</ref> <ref>PMID:9787168</ref> <ref>PMID:10027710</ref> <ref>PMID:10606881</ref> <ref>PMID:11895778</ref> <ref>PMID:15026311</ref> <ref>PMID:15180874</ref> <ref>PMID:15953011</ref> <ref>PMID:16607084</ref> <ref>PMID:18005151</ref> <ref>PMID:21668437</ref> <ref>PMID:21457405</ref> <ref>PMID:22016685</ref> <ref>PMID:22322133</ref> <ref>PMID:21999818</ref> <ref>PMID:22159456</ref>
== Function ==
[[http://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
A large unmet medical need exists for safer antithrombotic drugs because all currently approved anticoagulant agents interfere with hemostasis, leading to an increased risk of bleeding. Genetic and pharmacologic evidence in humans and animals suggests that reducing factor XI (FXI) levels has the potential to effectively prevent and treat thrombosis with a minimal risk of bleeding. We generated a fully human antibody (MAA868) that binds the catalytic domain of both FXI (zymogen) and activated FXI. Our structural studies show that MAA868 traps FXI and activated FXI in an inactive, zymogen-like conformation, explaining its equally high binding affinity for both forms of the enzyme. This binding mode allows the enzyme to be neutralized before entering the coagulation process, revealing a particularly attractive anticoagulant profile of the antibody. MAA868 exhibited favorable anticoagulant activity in mice with a dose-dependent protection from carotid occlusion in a ferric chloride-induced thrombosis model. MAA868 also caused robust and sustained anticoagulant activity in cynomolgus monkeys as assessed by activated partial thromboplastin time without any evidence of bleeding. Based on these preclinical findings, we conducted a first-in-human study in healthy subjects and showed that single subcutaneous doses of MAA868 were safe and well tolerated. MAA868 resulted in dose- and time-dependent robust and sustained prolongation of activated partial thromboplastin time and FXI suppression for up to 4 weeks or longer, supporting further clinical investigation as a potential once-monthly subcutaneous anticoagulant therapy.

MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulation in humans.,Koch AW, Schiering N, Melkko S, Ewert S, Salter J, Zhang Y, McCormack P, Yu J, Huang X, Chiu YH, Chen Z, Schleeger S, Horny G, DiPetrillo K, Muller L, Hein A, Villard F, Scharenberg M, Ramage P, Hassiepen U, Cote S, DeGagne J, Krantz C, Eder J, Stoll B, Kulmatycki K, Feldman DL, Hoffmann P, Basson CT, Frost RJA, Khder Y Blood. 2019 Mar 28;133(13):1507-1516. doi: 10.1182/blood-2018-10-880849. Epub, 2019 Jan 28. PMID:30692123<ref>PMID:30692123</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6r8x" style="background-color:#fffaf0;"></div>
== References ==
<references/>
TOC
</StructureSection>
[[Category: Coagulation factor XIa]]
[[Category: Large Structures]]
[[Category: Koch, A]]
[[Category: Schiering, N]]
[[Category: Antagonist]]
[[Category: Antibody]]
[[Category: Blood clotting]]
[[Category: Coagulation fxi]]
[[Category: Zymogen]]