View source for 5qtw


==FACTOR XIA IN COMPLEX WITH THE INHIBITOR methyl (2R,7S)-7-({(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}amino)-14-[(methoxycarbonyl)amino]-2,3,4,5,6,7-hexahydro-1H-8,11-epimino-1,9-benzodiazacyclotridecine-2-carboxylate==
<StructureSection load='5qtw' size='340' side='right'caption='[[5qtw]], [[Resolution|resolution]] 2.12&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5qtw]] is a 1 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=5QTW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5QTW FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.12&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=QLM:methyl+(9~{R},14~{S})-14-[[(~{E})-3-[5-chloranyl-2-(1,2,3,4-tetrazol-1-yl)phenyl]prop-2-enoyl]amino]-5-(methoxycarbonylamino)-8,16,18-triazatricyclo[13.2.1.0^{2,7}]octadeca-1(17),2,4,6,15-pentaene-9-carboxylate'>QLM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=5qtw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5qtw OCA], [https://pdbe.org/5qtw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5qtw RCSB], [https://www.ebi.ac.uk/pdbsum/5qtw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5qtw ProSAT]</span></td></tr>
</table>
== Disease ==
[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 ==
[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 ==
The discovery of orally bioavailable FXIa inhibitors has been a challenge. Herein, we describe our efforts to address this challenge by optimization of our imidazole-based macrocyclic series. Our optimization strategy focused on modifications to the P2 prime, macrocyclic amide linker, and the imidazole scaffold. Replacing the amide of the macrocyclic linker with amide isosteres led to the discovery of substituted amine linkers which not only maintained FXIa binding affinity but also improved oral exposure in rats. Combining the optimized macrocyclic amine linker with a pyridine scaffold afforded compounds 23 and 24 that were orally bioavailable, single-digit nanomolar FXIa inhibitors with excellent selectivity against relevant blood coagulation enzymes.

Orally bioavailable amine-linked macrocyclic inhibitors of factor XIa.,Fang T, Corte JR, Gilligan PJ, Jeon Y, Osuna H, Rossi KA, Myers JE Jr, Sheriff S, Lou Z, Zheng JJ, Harper TW, Bozarth JM, Wu Y, Luettgen JM, Seiffert DA, Wexler RR, Lam PYS Bioorg Med Chem Lett. 2020 Feb 15;30(4):126949. doi: 10.1016/j.bmcl.2020.126949. , Epub 2020 Jan 7. PMID:31932224<ref>PMID:31932224</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5qtw" style="background-color:#fffaf0;"></div>

==See Also==
*[[Factor XIa 3D structures|Factor XIa 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Sheriff S]]