6bto

From Proteopedia

(Difference between revisions)

Current revision

BMP1 complexed with (2~{S})-2-[[(1~{R},3~{S},4~{S})-2-[(2~{R})-2-[2-(oxidanylamino)-2-oxidanylidene-ethyl]heptanoyl]-2-azabicyclo[2.2.1]heptan-3-yl]carbonylamino]-2-phenyl-ethanoic acid

Structural highlights

6bto is a 2 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:	X-ray diffraction, Resolution 2.05Å
Ligands:	, , ,
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/6bto"

Categories: Homo sapiens | Large Structures | Gampe R | Shewchuk L

@@ Line 1: / Line 1: @@
-==BMP1 complexed with a hydroxymate - compound 9==
+==BMP1 complexed with (2~{S})-2-[[(1~{R},3~{S},4~{S})-2-[(2~{R})-2-[2-(oxidanylamino)-2-oxidanylidene-ethyl]heptanoyl]-2-azabicyclo[2.2.1]heptan-3-yl]carbonylamino]-2-phenyl-ethanoic acid==
-<StructureSection load='6bto' size='340' side='right' caption='[[6bto]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
+<StructureSection load='6bto' size='340' side='right'caption='[[6bto]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6bto]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BTO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BTO FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6bto]] is a 2 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=6BTO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BTO FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=E8P:(2~{S})-2-[[(1~{R},3~{S},4~{S})-2-[(2~{R})-2-[2-(oxidanylamino)-2-oxidanylidene-ethyl]heptanoyl]-2-azabicyclo[2.2.1]heptan-3-yl]carbonylamino]-2-phenyl-ethanoic+acid'>E8P</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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]] 2.05&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=E8P:(2S)-({[(1R,3S,4S)-2-{(2R)-2-[2-(hydroxyamino)-2-oxoethyl]heptanoyl}-2-azabicyclo[2.2.1]heptan-3-yl]carbonyl}amino)(phenyl)acetic+acid+(non-preferred+name)'>E8P</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=6bto FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bto OCA], [http://pdbe.org/6bto PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bto RCSB], [http://www.ebi.ac.uk/pdbsum/6bto PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bto 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=6bto FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bto OCA], [https://pdbe.org/6bto PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6bto RCSB], [https://www.ebi.ac.uk/pdbsum/6bto PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6bto ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/BMP1_HUMAN BMP1_HUMAN]] Defects in BMP1 are the cause of osteogenesis imperfecta 13 (OI13) [MIM:[http://omim.org/entry/614856 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.<ref>PMID:22482805</ref> <ref>PMID:22052668</ref>
+[https://www.uniprot.org/uniprot/BMP1_HUMAN BMP1_HUMAN] Defects in BMP1 are the cause of osteogenesis imperfecta 13 (OI13) [MIM:[https://omim.org/entry/614856 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.<ref>PMID:22482805</ref> <ref>PMID:22052668</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/BMP1_HUMAN 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.
+[https://www.uniprot.org/uniprot/BMP1_HUMAN 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.
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 21: @@
 </div>
 <div class="pdbe-citations 6bto" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Bone morphogenetic protein 3D structures|Bone morphogenetic protein 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Procollagen C-endopeptidase]]
+[[Category: Homo sapiens]]
-[[Category: Gampe, R]]
+[[Category: Large Structures]]
-[[Category: Shewchuk, L]]
+[[Category: Gampe R]]
-[[Category: Endopeptidase]]
+[[Category: Shewchuk L]]
-[[Category: Hydrolase]]

6bto

From Proteopedia

Current revision

BMP1 complexed with (2~{S})-2-[[(1~{R},3~{S},4~{S})-2-[(2~{R})-2-[2-(oxidanylamino)-2-oxidanylidene-ethyl]heptanoyl]-2-azabicyclo[2.2.1]heptan-3-yl]carbonylamino]-2-phenyl-ethanoic acid

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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