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3q77

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Revision as of 11:34, 17 July 2019

Structure of human neutrophil elastase in complex with a dihydropyrimidone inhibitor

Structural highlights

3q77 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	3q76
Activity:	Leukocyte elastase, with EC number 3.4.21.37
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[ELNE_HUMAN] Defects in ELANE are a cause of cyclic haematopoiesis (CH) [MIM:162800]; also known as cyclic neutropenia. CH is an autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency.^[1] ^[2] Defects in ELANE are the cause of neutropenia severe congenital autosomal dominant type 1 (SCN1) [MIM:202700]. SCN1 is a disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections.^[3]

Function

[ELNE_HUMAN] Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis.^[4]

Publication Abstract from PubMed

Human neutrophil elastase (HNE), a trypsin-type serine protease, is of pivotal importance in the onset and progression of chronic obstructive pulmonary disease (COPD). COPD encompasses a group of slowly progressive respiratory disorders and is a major medical problem and the fifth leading cause of death worldwide. HNE is a major target for the development of compounds that inhibit the progression of long-term lung function decline in COPD patients. Here, we present the three-dimensional structure of a potent dihydropyrimidone inhibitor (DHPI) non-covalently bound to HNE at a resolution of 2.0 A. The inhibitor binds to the active site in a unique orientation addressing S1 and S2 subsites of the protease. To facilitate further analysis of this binding mode, we determined the structure of the uncomplexed enzyme at a resolution of 1.86 A. Detailed comparisons of the HNE:DHPI complex with the uncomplexed HNE structure and published structures of other elastase:inhibitor complexes revealed that binding of DHPI leads to large conformational changes in residues located in the S2 subsite. The rearrangement of residues Asp95-Leu99B creates a deep, well-defined cavity, which is filled by the P2 moiety of the inhibitor molecule to almost perfect shape complementarity. The shape of the S2 subsite in complex with DHPI clearly differs from all other observed HNE structures. The observed structural flexibility of the S2 subsite is a key feature for the understanding of the binding mode of DHPIs in general and the development of new HNE selective inhibitors.

Unexpected Active-Site Flexibility in the Structure of Human Neutrophil Elastase in Complex with a New Dihydropyrimidone Inhibitor.,Hansen G, Gielen-Haertwig H, Reinemer P, Schomburg D, Harrenga A, Niefind K J Mol Biol. 2011 Apr 27. PMID:21549129^[5]

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

References

↑ Duan Z, Li FQ, Wechsler J, Meade-White K, Williams K, Benson KF, Horwitz M. A novel notch protein, N2N, targeted by neutrophil elastase and implicated in hereditary neutropenia. Mol Cell Biol. 2004 Jan;24(1):58-70. PMID:14673143
↑ Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet. 1999 Dec;23(4):433-6. PMID:10581030 doi:10.1038/70544
↑ Germeshausen M, Zeidler C, Stuhrmann M, Lanciotti M, Ballmaier M, Welte K. Digenic mutations in severe congenital neutropenia. Haematologica. 2010 Jul;95(7):1207-10. doi: 10.3324/haematol.2009.017665. Epub, 2010 Mar 10. PMID:20220065 doi:10.3324/haematol.2009.017665
↑ Tralau T, Meyer-Hoffert U, Schroder JM, Wiedow O. Human leukocyte elastase and cathepsin G are specific inhibitors of C5a-dependent neutrophil enzyme release and chemotaxis. Exp Dermatol. 2004 May;13(5):316-25. PMID:15140022 doi:10.1111/j.0906-6705.2004.00145.x
↑ Hansen G, Gielen-Haertwig H, Reinemer P, Schomburg D, Harrenga A, Niefind K. Unexpected Active-Site Flexibility in the Structure of Human Neutrophil Elastase in Complex with a New Dihydropyrimidone Inhibitor. J Mol Biol. 2011 Apr 27. PMID:21549129 doi:10.1016/j.jmb.2011.04.047

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/3q77"

@@ Line 1: / Line 1: @@
 ==Structure of human neutrophil elastase in complex with a dihydropyrimidone inhibitor==
-<StructureSection load='3q77' size='340' side='right' caption='[[3q77]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+<StructureSection load='3q77' size='340' side='right'caption='[[3q77]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[3q77]] is a 1 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=3Q77 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3Q77 FirstGlance]. <br>
@@ Line 24: / Line 24: @@
 ==See Also==
-*[[Elastase|Elastase]]
+*[[Elastase 3D structures|Elastase 3D structures]]
 == References ==
 <references/>
@@ Line 30: / Line 30: @@
 </StructureSection>
 [[Category: Homo sapiens]]
+[[Category: Large Structures]]
 [[Category: Leukocyte elastase]]
 [[Category: Hansen, G]]

3q77

From Proteopedia

Revision as of 11:34, 17 July 2019

Structure of human neutrophil elastase in complex with a dihydropyrimidone inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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