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4k1e

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Atomic resolution crystal structures of Kallikrein-Related Peptidase 4 complexed with a modified SFTI inhibitor FCQR

Structural highlights

4k1e is a 2 chain structure with sequence from Helianthus annuus and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.3Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

KLK4_HUMAN Defects in KLK4 are the cause of amelogenesis imperfecta hypomaturation type 2A1 (AI2A1) [MIM:204700. AI2A1 is an autosomal recessive defect of enamel formation. The disorder involves both primary and secondary dentitions. The teeth have a shiny agar jelly appearance and the enamel is softer than normal. Brown pigment is present in middle layers of enamel.^[1]

Function

KLK4_HUMAN Involved in enamel formation.^[2]

Publication Abstract from PubMed

The kallikrein-related peptidase (KLK) family of proteases is involved in many aspects of human health and disease. One member of this family, KLK4, has been implicated in cancer development and metastasis. Understanding mechanisms of inactivation are critical to developing selective KLK4 inhibitors. We have determined the X-ray crystal structures of KLK4 in complex with both sunflower trypsin inhibitor-1 (SFTI-1) and a rationally designed SFTI-1 derivative to atomic (~1 A) resolution, as well as with bound nickel. These structures offer a structural rationalization for the potency and selectivity of these inhibitors, and together with MD simulation and computational analysis, reveal a dynamic pathway between the metal binding exosite and the active site, providing key details of a previously proposed allosteric mode of inhibition. Collectively, this work provides insight into both direct and indirect mechanisms of inhibition for KLK4 that have broad implications for the enzymology of the serine protease superfamily, and may potentially be exploited for the design of therapeutic inhibitors.

Direct and indirect mechanisms of KLK4 inhibition revealed by structure and dynamics.,Riley BT, Ilyichova O, Costa MG, Porebski BT, de Veer SJ, Swedberg JE, Kass I, Harris JM, Hoke DE, Buckle AM Sci Rep. 2016 Oct 21;6:35385. doi: 10.1038/srep35385. PMID:27767076^[3]

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

References

↑ Hart PS, Hart TC, Michalec MD, Ryu OH, Simmons D, Hong S, Wright JT. Mutation in kallikrein 4 causes autosomal recessive hypomaturation amelogenesis imperfecta. J Med Genet. 2004 Jul;41(7):545-9. PMID:15235027
↑ Hart PS, Hart TC, Michalec MD, Ryu OH, Simmons D, Hong S, Wright JT. Mutation in kallikrein 4 causes autosomal recessive hypomaturation amelogenesis imperfecta. J Med Genet. 2004 Jul;41(7):545-9. PMID:15235027
↑ Riley BT, Ilyichova O, Costa MG, Porebski BT, de Veer SJ, Swedberg JE, Kass I, Harris JM, Hoke DE, Buckle AM. Direct and indirect mechanisms of KLK4 inhibition revealed by structure and dynamics. Sci Rep. 2016 Oct 21;6:35385. doi: 10.1038/srep35385. PMID:27767076 doi:http://dx.doi.org/10.1038/srep35385

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/4k1e"

@@ Line 1: / Line 1: @@
 ==Atomic resolution crystal structures of Kallikrein-Related Peptidase 4 complexed with a modified SFTI inhibitor FCQR==
-<StructureSection load='4k1e' size='340' side='right' caption='[[4k1e]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
+<StructureSection load='4k1e' size='340' side='right'caption='[[4k1e]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4k1e]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4K1E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4K1E FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4k1e]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Helianthus_annuus Helianthus annuus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4K1E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4K1E FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=LI:LITHIUM+ION'>LI</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</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]] 1.3&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2bdg|2bdg]], [[2bdi|2bdi]], [[2bdh|2bdh]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LI:LITHIUM+ION'>LI</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KLK4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4k1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k1e OCA], [https://pdbe.org/4k1e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4k1e RCSB], [https://www.ebi.ac.uk/pdbsum/4k1e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4k1e ProSAT]</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=4k1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k1e OCA], [http://pdbe.org/4k1e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4k1e RCSB], [http://www.ebi.ac.uk/pdbsum/4k1e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4k1e ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/KLK4_HUMAN KLK4_HUMAN]] Defects in KLK4 are the cause of amelogenesis imperfecta hypomaturation type 2A1 (AI2A1) [MIM:[http://omim.org/entry/204700 204700]]. AI2A1 is an autosomal recessive defect of enamel formation. The disorder involves both primary and secondary dentitions. The teeth have a shiny agar jelly appearance and the enamel is softer than normal. Brown pigment is present in middle layers of enamel.<ref>PMID:15235027</ref>
+[https://www.uniprot.org/uniprot/KLK4_HUMAN KLK4_HUMAN] Defects in KLK4 are the cause of amelogenesis imperfecta hypomaturation type 2A1 (AI2A1) [MIM:[https://omim.org/entry/204700 204700]. AI2A1 is an autosomal recessive defect of enamel formation. The disorder involves both primary and secondary dentitions. The teeth have a shiny agar jelly appearance and the enamel is softer than normal. Brown pigment is present in middle layers of enamel.<ref>PMID:15235027</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/KLK4_HUMAN KLK4_HUMAN]] Involved in enamel formation.<ref>PMID:15235027</ref>  [[http://www.uniprot.org/uniprot/SFTI1_HELAN SFTI1_HELAN]] Inhibits trypsin, cathepsin G, elastase, chymotrypsin and thrombin. Does not inhibit factor Xa.<ref>PMID:10390350</ref>
+[https://www.uniprot.org/uniprot/KLK4_HUMAN KLK4_HUMAN] Involved in enamel formation.<ref>PMID:15235027</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 21: @@
 </div>
 <div class="pdbe-citations 4k1e" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Kallikrein 3D structures|Kallikrein 3D structures]]
+*[[Trypsin inhibitor 3D structures|Trypsin inhibitor 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Helianthus annuus]]
-[[Category: Buckle, A M]]
+[[Category: Homo sapiens]]
-[[Category: Harris, J M]]
+[[Category: Large Structures]]
-[[Category: Ilyichova, O V]]
+[[Category: Buckle AM]]
-[[Category: Sit, K C]]
+[[Category: Harris JM]]
-[[Category: Swedberg, J E]]
+[[Category: Ilyichova OV]]
-[[Category: Veer, S J.de]]
+[[Category: Sit KC]]
-[[Category: Bowman-birk inhibitor]]
+[[Category: Swedberg JE]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]
+[[Category: De Veer SJ]]
-[[Category: Protease]]
-[[Category: Protease inhibitor]]
-[[Category: Protein-peptide complex]]

4k1e

From Proteopedia

Current revision

Atomic resolution crystal structures of Kallikrein-Related Peptidase 4 complexed with a modified SFTI inhibitor FCQR

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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