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6bsl

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BMP1 complexed with a reverse hydroxymate - compound 22

Structural highlights

6bsl is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
NonStd Res:
Activity:	Procollagen C-endopeptidase, with EC number 3.4.24.19
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[BMP1_HUMAN] Defects in BMP1 are the cause of osteogenesis imperfecta 13 (OI13) [MIM:614856]. An autosomal recessive form of osteogenesis imperfecta, a connective tissue disorder characterized by bone fragility, low bone mass, and recurrent fractures. OI13 is characterized by normal teeth, faint blue sclerae, severe growth deficiency, borderline osteoporosis, severe bone deformity, and recurrent fractures affecting both upper and lower limbs.^[1] ^[2]

Function

[BMP1_HUMAN] Cleaves the C-terminal propeptides of procollagen I, II and III. Induces cartilage and bone formation. May participate in dorsoventral patterning during early development by cleaving chordin (CHRD). Responsible for the proteolytic activation of lysyl oxidase LOX.

Publication Abstract from PubMed

Bone Morphogenetic Protein 1 (BMP1) inhibition is a potential method for treating fibrosis because BMP1, a member of the zinc metalloprotease family, is required to convert pro-collagen to collagen. A novel class of reverse hydroxamate BMP1 inhibitors was discovered, and cocrystal structures with BMP1 were obtained. The observed binding mode is unique in that the small molecule occupies the nonprime side of the metalloprotease pocket providing an opportunity to build in metalloprotease selectivity. Structure-guided modification of the initial hit led to the identification of an oral in vivo tool compound with selectivity over other metalloproteases. Due to irreversible inhibition of cytochrome P450 3A4 for this chemical class, the risk of potential drug-drug interactions was managed by optimizing the series for subcutaneous injection.

Reverse Hydroxamate Inhibitors of Bone Morphogenetic Protein 1.,Kallander LS, Washburn D, Hilfiker MA, Eidam HS, Lawhorn BG, Prendergast J, Fox R, Dowdell S, Manns S, Hoang T, Zhao S, Ye G, Hammond M, Holt DA, Roethke T, Hong X, Reid RA, Gampe R, Zhang H, Diaz E, Rendina AR, Quinn AM, Willette B ACS Med Chem Lett. 2018 Jul 2;9(7):736-740. doi: 10.1021/acsmedchemlett.8b00173. , eCollection 2018 Jul 12. PMID:30034610^[3]

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

References

↑ Asharani PV, Keupp K, Semler O, Wang W, Li Y, Thiele H, Yigit G, Pohl E, Becker J, Frommolt P, Sonntag C, Altmuller J, Zimmermann K, Greenspan DS, Akarsu NA, Netzer C, Schonau E, Wirth R, Hammerschmidt M, Nurnberg P, Wollnik B, Carney TJ. Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish. Am J Hum Genet. 2012 Apr 6;90(4):661-74. doi: 10.1016/j.ajhg.2012.02.026. PMID:22482805 doi:10.1016/j.ajhg.2012.02.026
↑ Martinez-Glez V, Valencia M, Caparros-Martin JA, Aglan M, Temtamy S, Tenorio J, Pulido V, Lindert U, Rohrbach M, Eyre D, Giunta C, Lapunzina P, Ruiz-Perez VL. Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta. Hum Mutat. 2012 Feb;33(2):343-50. doi: 10.1002/humu.21647. Epub 2011 Nov 30. PMID:22052668 doi:10.1002/humu.21647
↑ Kallander LS, Washburn D, Hilfiker MA, Eidam HS, Lawhorn BG, Prendergast J, Fox R, Dowdell S, Manns S, Hoang T, Zhao S, Ye G, Hammond M, Holt DA, Roethke T, Hong X, Reid RA, Gampe R, Zhang H, Diaz E, Rendina AR, Quinn AM, Willette B. Reverse Hydroxamate Inhibitors of Bone Morphogenetic Protein 1. ACS Med Chem Lett. 2018 Jul 2;9(7):736-740. doi: 10.1021/acsmedchemlett.8b00173. , eCollection 2018 Jul 12. PMID:30034610 doi:http://dx.doi.org/10.1021/acsmedchemlett.8b00173

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6bsl"

@@ Line 1: / Line 1: @@
 ==BMP1 complexed with a reverse hydroxymate - compound 22==
-<StructureSection load='6bsl' size='340' side='right' caption='[[6bsl]], [[Resolution|resolution]] 1.45&Aring;' scene=''>
+<StructureSection load='6bsl' size='340' side='right'caption='[[6bsl]], [[Resolution|resolution]] 1.45&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6bsl]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BSL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BSL FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6bsl]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BSL OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6BSL FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=EVV:N-(2-ethoxy-4-{5-[({[(2R)-2-{(1R)-1-[formyl(hydroxy)amino]propyl}heptanoyl]amino}methyl)carbamoyl]furan-2-yl}benzene-1-carbonyl)-L-aspartic+acid'>EVV</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</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=EVV:N-(2-ethoxy-4-{5-[({[(2R)-2-{(1R)-1-[formyl(hydroxy)amino]propyl}heptanoyl]amino}methyl)carbamoyl]furan-2-yl}benzene-1-carbonyl)-L-aspartic+acid'>EVV</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene></td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Procollagen_C-endopeptidase Procollagen C-endopeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.19 3.4.24.19] </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=6bsl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bsl OCA], [http://pdbe.org/6bsl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bsl RCSB], [http://www.ebi.ac.uk/pdbsum/6bsl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bsl ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6bsl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bsl OCA], [http://pdbe.org/6bsl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bsl RCSB], [http://www.ebi.ac.uk/pdbsum/6bsl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bsl ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 22: / Line 22: @@
 </div>
 <div class="pdbe-citations 6bsl" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Bone morphogenetic protein 3D structures|Bone morphogenetic protein 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Procollagen C-endopeptidase]]
 [[Category: Gampe, R]]

6bsl

From Proteopedia

Current revision

BMP1 complexed with a reverse hydroxymate - compound 22

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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