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| | <StructureSection load='6o21' size='340' side='right'caption='[[6o21]], [[Resolution|resolution]] 1.15Å' scene=''> | | <StructureSection load='6o21' size='340' side='right'caption='[[6o21]], [[Resolution|resolution]] 1.15Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6o21]] 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=6O21 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O21 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6o21]] 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=6O21 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6O21 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</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]] 1.15Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KLK4, KLNB1, hCG_1641510 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=PRD_001059:Trypsin+inhibitor+1'>PRD_001059</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=6o21 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o21 OCA], [http://pdbe.org/6o21 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o21 RCSB], [http://www.ebi.ac.uk/pdbsum/6o21 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o21 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=6o21 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o21 OCA], [https://pdbe.org/6o21 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6o21 RCSB], [https://www.ebi.ac.uk/pdbsum/6o21 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6o21 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Disease == |
| | + | [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 == |
| | + | [https://www.uniprot.org/uniprot/KLK4_HUMAN KLK4_HUMAN] Involved in enamel formation.<ref>PMID:15235027</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6o21" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6o21" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Kallikrein 3D structures|Kallikrein 3D structures]] |
| | + | *[[Trypsin inhibitor 3D structures|Trypsin inhibitor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Helianthus annuus]] |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Buckle, A M]] | + | [[Category: Buckle AM]] |
| - | [[Category: Ilyichova, O V]] | + | [[Category: Ilyichova OV]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Kallikrein-related peptidase 4]]
| + | |
| - | [[Category: Klk4]]
| + | |
| - | [[Category: Laskowski mechanism inhibitor]]
| + | |
| - | [[Category: Sfti]]
| + | |
| - | [[Category: Sunflower trypsin inhibitor]]
| + | |
| Structural highlights
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
Sunflower trypsin inhibitor (SFTI-1) is a 14 amino acid serine protease inhibitor. The dual antiparallel beta-sheet arrangement of SFTI-1 is stabilized by an N-terminal-C-terminal backbone cyclization and a further disulfide bridge to form a final bicyclic structure. This constrained structure is further rigidified by an extensive network of internal hydrogen bonds. Thus, the structure of SFTI-1 in solution resembles the protease-bound structure, reducing the entropic penalty upon protease binding. When cleaved at the scissile bond, it is thought that the rigidifying features of SFTI-1 maintain its structure, allowing the scissile bond to be reformed. The lack of structural plasticity for SFTI-1 is proposed to favor initial protease binding and continued occupancy in the protease active site, resulting in an equilibrium between the cleaved and uncleaved inhibitor in the presence of a protease. We have determined, at 1.15 A resolution, the X-ray crystal structures of complexes between human kallikrein-related peptidase 4 (KLK4) and SFTI-FCQR(Asn14) and between KLK4 and an acyclic form of the same inhibitor, SFTI-FCQR(Asn14)[1,14], with the latter displaying a cleaved scissile bond. Structural analysis and MD simulations together reveal the roles of the altered contact sequence, intramolecular hydrogen bonding network, and backbone cyclization in altering the state of SFTI's scissile bond ligation at the protease active site. Taken together, the data presented reveal insights into the role of dynamics in the standard-mechanism inhibition and suggest that modifications on the non-contact strand may be a useful, underexplored approach for generating further potent or selective SFTI-based inhibitors against members of the serine protease family.
KLK4 Inhibition by Cyclic and Acyclic Peptides: Structural and Dynamical Insights into Standard-Mechanism Protease Inhibitors.,Riley BT, Ilyichova O, de Veer SJ, Swedberg JE, Wilson E, Hoke DE, Harris JM, Buckle AM Biochemistry. 2019 May 28;58(21):2524-2533. doi: 10.1021/acs.biochem.9b00191., Epub 2019 May 13. PMID:31058493[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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, de Veer SJ, Swedberg JE, Wilson E, Hoke DE, Harris JM, Buckle AM. KLK4 Inhibition by Cyclic and Acyclic Peptides: Structural and Dynamical Insights into Standard-Mechanism Protease Inhibitors. Biochemistry. 2019 May 28;58(21):2524-2533. doi: 10.1021/acs.biochem.9b00191., Epub 2019 May 13. PMID:31058493 doi:http://dx.doi.org/10.1021/acs.biochem.9b00191
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