| Structural highlights
6bh8 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Related: | 5syt, 4aw6, 2ypt |
| Gene: | ZMPSTE24, FACE1, STE24 (HUMAN) |
| Activity: | Ste24 endopeptidase, with EC number 3.4.24.84 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[FACE1_HUMAN] Mandibuloacral dysplasia with type B lipodystrophy;Hutchinson-Gilford progeria syndrome;Lethal restrictive dermopathy. Mandibuloacral dysplasia with type B lipodystrophy (MADB) [MIM:608612]: A disorder characterized by mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of the cranial suture, joint contractures, and generalized lipodystrophy with loss of subcutaneous fat from the extremities, face, neck and trunk. Note=The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3] [4] Lethal tight skin contracture syndrome (LTSCS) [MIM:275210]: Rare disorder mainly characterized by intrauterine growth retardation, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, facial features (small mouth, small pinched nose and micrognathia), sparse/absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia, multiple joint contractures and an early neonatal lethal course. Liveborn children usually die within the first week of life. The overall prevalence of consanguineous cases suggested an autosomal recessive inheritance. Note=The disease is caused by mutations affecting the gene represented in this entry.[5]
Function
[FACE1_HUMAN] Proteolytically removes the C-terminal three residues of farnesylated proteins. Acts on lamin A/C.
Publication Abstract from PubMed
The integral membrane protein zinc metalloprotease ZMPSTE24 possesses a completely novel structure, comprising seven long kinked transmembrane helices that encircle a voluminous 14 000 A(3) cavity within the membrane. Functionally conserved soluble zinc metalloprotease residues are contained within this cavity. As part of an effort to understand the structural and functional relationships between ZMPSTE24 and soluble zinc metalloproteases, the inhibition of ZMPSTE24 by phosphoramidon [N-(alpha-rhamnopyranosyl-oxyhydroxyphosphinyl)-Leu-Trp], a transition-state analog and competitive inhibitor of multiple soluble zinc metalloproteases, especially gluzincins, has been characterized functionally and structurally. The functional results, the determination of preliminary IC50 values by the use of an intramolecular quenched-fluorescence fluorogenic peptide assay, indicate that phosphoramidon inhibits ZMPSTE24 in a manner consistent with competitive inhibition. The structural results, a 3.85 A resolution X-ray crystal structure of a ZMPSTE24-phosphoramidon complex, indicate that the overall binding mode observed between phosphoramidon and soluble gluzincins is conserved. Based on the structural data, a significantly lower potency than that observed for soluble gluzincins such as thermolysin and neprilysin is predicted. These results strongly suggest a close relationship between soluble gluzincins and the integral membrane protein zinc metalloprotease ZMPSTE24.
Phosphoramidon inhibits the integral membrane protein zinc metalloprotease ZMPSTE24.,Goblirsch BR, Arachea BT, Councell DJ, Wiener MC Acta Crystallogr D Struct Biol. 2018 Aug 1;74(Pt 8):739-747. doi:, 10.1107/S2059798318003431. Epub 2018 Jul 24. PMID:30082509[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Agarwal AK, Fryns JP, Auchus RJ, Garg A. Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet. 2003 Aug 15;12(16):1995-2001. PMID:12913070
- ↑ Agarwal AK, Zhou XJ, Hall RK, Nicholls K, Bankier A, Van Esch H, Fryns JP, Garg A. Focal segmental glomerulosclerosis in patients with mandibuloacral dysplasia owing to ZMPSTE24 deficiency. J Investig Med. 2006 May;54(4):208-13. PMID:17152860
- ↑ Miyoshi Y, Akagi M, Agarwal AK, Namba N, Kato-Nishimura K, Mohri I, Yamagata M, Nakajima S, Mushiake S, Shima M, Auchus RJ, Taniike M, Garg A, Ozono K. Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings. Clin Genet. 2008 Jun;73(6):535-44. doi: 10.1111/j.1399-0004.2008.00992.x. Epub, 2008 Apr 22. PMID:18435794 doi:10.1111/j.1399-0004.2008.00992.x
- ↑ Ahmad Z, Zackai E, Medne L, Garg A. Early onset mandibuloacral dysplasia due to compound heterozygous mutations in ZMPSTE24. Am J Med Genet A. 2010 Nov;152A(11):2703-10. doi: 10.1002/ajmg.a.33664. PMID:20814950 doi:10.1002/ajmg.a.33664
- ↑ Navarro CL, De Sandre-Giovannoli A, Bernard R, Boccaccio I, Boyer A, Genevieve D, Hadj-Rabia S, Gaudy-Marqueste C, Smitt HS, Vabres P, Faivre L, Verloes A, Van Essen T, Flori E, Hennekam R, Beemer FA, Laurent N, Le Merrer M, Cau P, Levy N. Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy. Hum Mol Genet. 2004 Oct 15;13(20):2493-503. Epub 2004 Aug 18. PMID:15317753 doi:10.1093/hmg/ddh265
- ↑ Goblirsch BR, Arachea BT, Councell DJ, Wiener MC. Phosphoramidon inhibits the integral membrane protein zinc metalloprotease ZMPSTE24. Acta Crystallogr D Struct Biol. 2018 Aug 1;74(Pt 8):739-747. doi:, 10.1107/S2059798318003431. Epub 2018 Jul 24. PMID:30082509 doi:http://dx.doi.org/10.1107/S2059798318003431
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