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|1huw, resolution 2.00Å ()|
THE CRYSTAL STRUCTURE OF AFFINITY-MATURED HUMAN GROWTH HORMONE AT 2 ANGSTROMS RESOLUTION
A variant of human growth hormone (hGH), in which 15 mutations were introduced with phage display mutagenesis to improve receptor binding affinity by 400-fold, yielded two related crystal forms diffracting to high resolution. The structure of this variant was determined in both crystal forms, one at 2.0 A resolution and one at 2.4 A resolution, using molecular replacement with wild-type hGH taken from the receptor complex structure as a search model. Crystallographic refinement of the 2 A structure gave an R-value R-value of 18.5% for data in the resolution range 8 to 2 A. The final model consists of residues 1 to 128 and 155 to 191, with three side-chains modeled in alternative conformations, together with 77 water molecules. Comparison of the structure with wild-type hGH shows that most of the secondary structural elements are unchanged. The exception is the first turn of the third helix in the four-helix bundle core, which is unraveled in the present variant. Analysis of the two related packing environments suggests that this change is caused by crystal packing forces. A large change in the orientation of a short segment of helix found in the connection between the first two core helices is interpreted as evidence for rigid-body variability of this helical segment. Analysis of the mutations in light of the structure of the wild-type hGH/receptor complex shows that six of the mutations are buried in the hormone, whereas the remaining nine involve residues that interact with the receptor in the complex.
The crystal structure of affinity-matured human growth hormone at 2 A resolution., Ultsch MH, Somers W, Kossiakoff AA, de Vos AM, J Mol Biol. 1994 Feb 11;236(1):286-99. PMID:8107110
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[SOMA_HUMAN] Defects in GH1 are a cause of growth hormone deficiency isolated type 1A (IGHD1A) [MIM:262400]; also known as pituitary dwarfism I. IGHD1A is an autosomal recessive deficiency of GH which causes short stature. IGHD1A patients have an absence of GH with severe dwarfism and often develop anti-GH antibodies when given exogenous GH. Defects in GH1 are a cause of growth hormone deficiency isolated type 1B (IGHD1B) [MIM:612781]; also known as dwarfism of Sindh. IGHD1B is an autosomal recessive deficiency of GH which causes short stature. IGHD1B patients have low but detectable levels of GH. Dwarfism is less severe than in IGHD1A and patients usually respond well to exogenous GH. Defects in GH1 are the cause of Kowarski syndrome (KWKS) [MIM:262650]; also known as pituitary dwarfism VI. Defects in GH1 are a cause of growth hormone deficiency isolated type 2 (IGHD2) [MIM:173100]. IGHD2 is an autosomal dominant deficiency of GH which causes short stature. Clinical severity is variable. Patients have a positive response and immunologic tolerance to growth hormone therapy.
[SOMA_HUMAN] Plays an important role in growth control. Its major role in stimulating body growth is to stimulate the liver and other tissues to secrete IGF-1. It stimulates both the differentiation and proliferation of myoblasts. It also stimulates amino acid uptake and protein synthesis in muscle and other tissues.
About this Structure
- Ultsch MH, Somers W, Kossiakoff AA, de Vos AM. The crystal structure of affinity-matured human growth hormone at 2 A resolution. J Mol Biol. 1994 Feb 11;236(1):286-99. PMID:8107110 doi:http://dx.doi.org/10.1006/jmbi.1994.1135
- Gomez-Orellana I, Variano B, Miura-Fraboni J, Milstein S, Paton DR. Thermodynamic characterization of an intermediate state of human growth hormone. Protein Sci. 1998 Jun;7(6):1352-8. PMID:9655339 doi:10.1002/pro.5560070611
- Hill EE, Morea V, Chothia C. Sequence conservation in families whose members have little or no sequence similarity: the four-helical cytokines and cytochromes. J Mol Biol. 2002 Sep 6;322(1):205-33. PMID:12215425
- ↑ Igarashi Y, Ogawa M, Kamijo T, Iwatani N, Nishi Y, Kohno H, Masumura T, Koga J. A new mutation causing inherited growth hormone deficiency: a compound heterozygote of a 6.7 kb deletion and a two base deletion in the third exon of the GH-1 gene. Hum Mol Genet. 1993 Jul;2(7):1073-4. PMID:8364549
- ↑ Takahashi Y, Kaji H, Okimura Y, Goji K, Abe H, Chihara K. Brief report: short stature caused by a mutant growth hormone. N Engl J Med. 1996 Feb 15;334(7):432-6. PMID:8552145 doi:http://dx.doi.org/10.1056/NEJM199602153340704
- ↑ Takahashi Y, Shirono H, Arisaka O, Takahashi K, Yagi T, Koga J, Kaji H, Okimura Y, Abe H, Tanaka T, Chihara K. Biologically inactive growth hormone caused by an amino acid substitution. J Clin Invest. 1997 Sep 1;100(5):1159-65. PMID:9276733 doi:10.1172/JCI119627
- ↑ Petkovic V, Besson A, Thevis M, Lochmatter D, Eble A, Fluck CE, Mullis PE. Evaluation of the biological activity of a growth hormone (GH) mutant (R77C) and its impact on GH responsiveness and stature. J Clin Endocrinol Metab. 2007 Aug;92(8):2893-901. Epub 2007 May 22. PMID:17519310 doi:10.1210/jc.2006-2238