6skb

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Crystal Structure of Human Kallikrein 6 (N217D/I218Y/K224R) in complex with GSK3496783ACrystal Structure of Human Kallikrein 6 (N217D/I218Y/K224R) in complex with GSK3496783A

Structural highlights

6skb is a 3 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 1.84Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KLK6_HUMAN Serine protease which exhibits a preference for Arg over Lys in the substrate P1 position and for Ser or Pro in the P2 position. Shows activity against amyloid precursor protein, myelin basic protein, gelatin, casein and extracellular matrix proteins such as fibronectin, laminin, vitronectin and collagen. Degrades alpha-synuclein and prevents its polymerization, indicating that it may be involved in the pathogenesis of Parkinson disease and other synucleinopathies. May be involved in regulation of axon outgrowth following spinal cord injury. Tumor cells treated with a neutralizing KLK6 antibody migrate less than control cells, suggesting a role in invasion and metastasis.[1] [2] [3] [4] [5] [6]

Publication Abstract from PubMed

The connection between Netherton syndrome and overactivation of epidermal/dermal proteases, particularly Kallikrein 5 (KLK5) has been well established and it is expected that a KLK5 inhibitor would improve the dermal barrier and also reduce the pain and itch that afflict Netherton syndrome patients. One of the challenges of covalent protease inhibitors has been achieving selectivity over closely related targets. In this paper we describe the use of structural insight to design and develop a selective and highly potent reversibly covalent KLK5 inhibitor from an initial weakly binding fragment.

Design and development of a series of borocycles as selective, covalent kallikrein 5 inhibitors.,Walker AL, Denis A, Bingham RP, Bouillot A, Edgar EV, Ferrie A, Holmes DS, Laroze A, Liddle J, Fouchet MH, Moquette A, Nassau P, Pearce AC, Polyakova O, Smith KJ, Thomas P, Thorpe JH, Trottet L, Wang Y, Hovnanian A Bioorg Med Chem Lett. 2019 Oct 15;29(20):126675. doi: 10.1016/j.bmcl.2019.126675. , Epub 2019 Sep 7. PMID:31521475[7]

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

See Also

References

  1. ↑ Magklara A, Mellati AA, Wasney GA, Little SP, Sotiropoulou G, Becker GW, Diamandis EP. Characterization of the enzymatic activity of human kallikrein 6: Autoactivation, substrate specificity, and regulation by inhibitors. Biochem Biophys Res Commun. 2003 Aug 8;307(4):948-55. PMID:12878203
  2. ↑ Iwata A, Maruyama M, Akagi T, Hashikawa T, Kanazawa I, Tsuji S, Nukina N. Alpha-synuclein degradation by serine protease neurosin: implication for pathogenesis of synucleinopathies. Hum Mol Genet. 2003 Oct 15;12(20):2625-35. Epub 2003 Aug 19. PMID:12928483 doi:http://dx.doi.org/10.1093/hmg/ddg283
  3. ↑ Ghosh MC, Grass L, Soosaipillai A, Sotiropoulou G, Diamandis EP. Human kallikrein 6 degrades extracellular matrix proteins and may enhance the metastatic potential of tumour cells. Tumour Biol. 2004 Jul-Aug;25(4):193-9. PMID:15557757 doi:http://dx.doi.org/10.1159/000081102
  4. ↑ Scarisbrick IA, Sabharwal P, Cruz H, Larsen N, Vandell AG, Blaber SI, Ameenuddin S, Papke LM, Fehlings MG, Reeves RK, Blaber M, Windebank AJ, Rodriguez M. Dynamic role of kallikrein 6 in traumatic spinal cord injury. Eur J Neurosci. 2006 Sep;24(5):1457-69. PMID:16987227 doi:http://dx.doi.org/10.1111/j.1460-9568.2006.05021.x
  5. ↑ Angelo PF, Lima AR, Alves FM, Blaber SI, Scarisbrick IA, Blaber M, Juliano L, Juliano MA. Substrate specificity of human kallikrein 6: salt and glycosaminoglycan activation effects. J Biol Chem. 2006 Feb 10;281(6):3116-26. Epub 2005 Dec 1. PMID:16321973 doi:http://dx.doi.org/M510096200
  6. ↑ Bernett MJ, Blaber SI, Scarisbrick IA, Dhanarajan P, Thompson SM, Blaber M. Crystal structure and biochemical characterization of human kallikrein 6 reveals that a trypsin-like kallikrein is expressed in the central nervous system. J Biol Chem. 2002 Jul 5;277(27):24562-70. Epub 2002 Apr 30. PMID:11983703 doi:10.1074/jbc.M202392200
  7. ↑ Walker AL, Denis A, Bingham RP, Bouillot A, Edgar EV, Ferrie A, Holmes DS, Laroze A, Liddle J, Fouchet MH, Moquette A, Nassau P, Pearce AC, Polyakova O, Smith KJ, Thomas P, Thorpe JH, Trottet L, Wang Y, Hovnanian A. Design and development of a series of borocycles as selective, covalent kallikrein 5 inhibitors. Bioorg Med Chem Lett. 2019 Oct 15;29(20):126675. PMID:31521475 doi:10.1016/j.bmcl.2019.126675

6skb, resolution 1.84Å

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