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6qbg

From Proteopedia

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Current revision

Crystal structure of human cathepsin D in complex with macrocyclic inhibitor 14

Structural highlights

6qbg 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 1.8Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CATD_HUMAN Defects in CTSD are the cause of neuronal ceroid lipofuscinosis type 10 (CLN10) [MIM:610127; also known as neuronal ceroid lipofuscinosis due to cathepsin D deficiency. A form of neuronal ceroid lipofuscinosis with onset at birth or early childhood. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy.^[1] ^[2] ^[3]

Function

CATD_HUMAN Acid protease active in intracellular protein breakdown. Involved in the pathogenesis of several diseases such as breast cancer and possibly Alzheimer disease.

Publication Abstract from PubMed

Human cathepsin D (CatD), a pepsin-family aspartic protease, plays an important role in tumor progression and metastasis. Here, we report the development of biomimetic inhibitors of CatD as novel tools for regulation of this therapeutic target. We designed a macrocyclic scaffold to mimic the spatial conformation of the minimal pseudo-dipeptide binding motif of pepstatin A, a microbial oligopeptide inhibitor, in the CatD active site. A library of more than 30 macrocyclic peptidomimetic inhibitors was employed for scaffold optimization, mapping of subsite interactions, and profiling of inhibitor selectivity. Furthermore, we solved high-resolution crystal structures of three macrocyclic inhibitors with low nanomolar or subnanomolar potency in complex with CatD and determined their binding mode using quantum chemical calculations. The study provides a new structural template and functional profile that can be exploited for design of potential chemotherapeutics that specifically inhibit CatD and related aspartic proteases.

Biomimetic Macrocyclic Inhibitors of Human Cathepsin D: Structure-Activity Relationship and Binding Mode Analysis.,Houstecka R, Hadzima M, Fanfrlik J, Brynda J, Pallova L, Hanova I, Mertlikova-Kaiserova H, Lepsik M, Horn M, Smrcina M, Majer P, Mares M J Med Chem. 2020 Feb 13. doi: 10.1021/acs.jmedchem.9b01351. PMID:32003991^[4]

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

References

↑ Siintola E, Partanen S, Stromme P, Haapanen A, Haltia M, Maehlen J, Lehesjoki AE, Tyynela J. Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain. 2006 Jun;129(Pt 6):1438-45. Epub 2006 May 2. PMID:16670177 doi:10.1093/brain/awl107
↑ Steinfeld R, Reinhardt K, Schreiber K, Hillebrand M, Kraetzner R, Bruck W, Saftig P, Gartner J. Cathepsin D deficiency is associated with a human neurodegenerative disorder. Am J Hum Genet. 2006 Jun;78(6):988-98. Epub 2006 Mar 29. PMID:16685649 doi:10.1086/504159
↑ Kousi M, Lehesjoki AE, Mole SE. Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Hum Mutat. 2012 Jan;33(1):42-63. doi: 10.1002/humu.21624. Epub 2011 Nov 16. PMID:21990111 doi:10.1002/humu.21624
↑ Houstecka R, Hadzima M, Fanfrlik J, Brynda J, Pallova L, Hanova I, Mertlikova-Kaiserova H, Lepsik M, Horn M, Smrcina M, Majer P, Mares M. Biomimetic Macrocyclic Inhibitors of Human Cathepsin D: Structure-Activity Relationship and Binding Mode Analysis. J Med Chem. 2020 Feb 13. doi: 10.1021/acs.jmedchem.9b01351. PMID:32003991 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01351

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/6qbg"

@@ Line 3: / Line 3: @@
 <StructureSection load='6qbg' size='340' side='right'caption='[[6qbg]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6qbg]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QBG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6QBG FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6qbg]] 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=6QBG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QBG FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=HVT:(3~{S},7~{S},8~{S})-8-(naphthalen-2-ylmethyl)-7-oxidanyl-3-propan-2-yl-1,4,9-triazacyclohenicosane-2,5,10-trione'>HVT</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.8&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cathepsin_D Cathepsin D], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.5 3.4.23.5] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=HVT:(3~{S},7~{S},8~{S})-8-(naphthalen-2-ylmethyl)-7-oxidanyl-3-propan-2-yl-1,4,9-triazacyclohenicosane-2,5,10-trione'>HVT</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6qbg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qbg OCA], [http://pdbe.org/6qbg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6qbg RCSB], [http://www.ebi.ac.uk/pdbsum/6qbg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6qbg 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=6qbg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qbg OCA], [https://pdbe.org/6qbg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qbg RCSB], [https://www.ebi.ac.uk/pdbsum/6qbg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qbg ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/CATD_HUMAN CATD_HUMAN]] Defects in CTSD are the cause of neuronal ceroid lipofuscinosis type 10 (CLN10) [MIM:[http://omim.org/entry/610127 610127]]; also known as neuronal ceroid lipofuscinosis due to cathepsin D deficiency. A form of neuronal ceroid lipofuscinosis with onset at birth or early childhood. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy.<ref>PMID:16670177</ref> <ref>PMID:16685649</ref> <ref>PMID:21990111</ref>
+[https://www.uniprot.org/uniprot/CATD_HUMAN CATD_HUMAN] Defects in CTSD are the cause of neuronal ceroid lipofuscinosis type 10 (CLN10) [MIM:[https://omim.org/entry/610127 610127]; also known as neuronal ceroid lipofuscinosis due to cathepsin D deficiency. A form of neuronal ceroid lipofuscinosis with onset at birth or early childhood. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy.<ref>PMID:16670177</ref> <ref>PMID:16685649</ref> <ref>PMID:21990111</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/CATD_HUMAN CATD_HUMAN]] Acid protease active in intracellular protein breakdown. Involved in the pathogenesis of several diseases such as breast cancer and possibly Alzheimer disease.
+[https://www.uniprot.org/uniprot/CATD_HUMAN CATD_HUMAN] Acid protease active in intracellular protein breakdown. Involved in the pathogenesis of several diseases such as breast cancer and possibly Alzheimer disease.
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 21: @@
 </div>
 <div class="pdbe-citations 6qbg" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Cathepsin 3D structures|Cathepsin 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Cathepsin D]]
 [[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Brynda, J]]
+[[Category: Brynda J]]
-[[Category: Houstecka, R]]
+[[Category: Houstecka R]]
-[[Category: Majer, P]]
+[[Category: Majer P]]
-[[Category: Mares, M]]
+[[Category: Mares M]]
-[[Category: Aspartic protease]]
-[[Category: Hydrolase]]
-[[Category: Peptidomimetic inhibitor]]

6qbg

From Proteopedia

Current revision

Crystal structure of human cathepsin D in complex with macrocyclic inhibitor 14

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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