1a22 | pdb_00001a22
HUMAN GROWTH HORMONE BOUND TO SINGLE RECEPTOR
Structural highlights
DiseaseSOMA_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.[1] 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.[2] [3] [4] 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. FunctionSOMA_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. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe designed G120R mutant of human growth hormone (hGH) is an antagonist and can bind only one molecule of the growth hormone receptor. We have determined the crystal structure of the 1:1 complex between this mutant and the receptor extracellular domain (hGHbp) at 2.6 A resolution, and used it to guide a detailed survey of the structural and functional basis for hormone-receptor recognition. The overall structure of the complex is very similar to the equivalent portion of the 1:2 complex, showing that formation of the active complex does not involve major conformational changes. However, a segment involved in receptor-receptor interactions in the 1:2 complex is disordered in this structure, suggesting that its productive conformation is stabilized by receptor dimerization. The hormone binding site of the receptor comprises a central hydrophobic patch dominated by Trp104 and Trp169, surrounded by a hydrophilic periphery containing several well-ordered water molecules. Previous alanine scanning showed that the hydrophobic "hot spot" confers most of the binding energy. The new structural data, coupled with binding and kinetic analysis of further mutants, indicate that the hot spot is assembled cooperatively and that many residues contribute indirectly to binding. Several hydrophobic residues serve to orient the key tryptophan residues; kinetic analysis suggests that Pro106 locks the Trp104 main-chain into a required conformation. The electrostatic contacts of Arg43 to hGH are less important than the intramolecular packing of its alkyl chain with Trp169. The true functional epitope that directly contributes binding energy may therefore comprise as few as six side-chains, participating mostly in alkyl-aromatic stacking interactions. Outside the functional epitope, multiple mutation of residues to alanine resulted in non-additive increases in affinity: up to tenfold for a hepta-alanine mutant. Contacts in the epitope periphery can therefore attenuate the affinity of the central hot spot, perhaps reflecting a role in conferring specificity to the interaction. Structural and functional analysis of the 1:1 growth hormone:receptor complex reveals the molecular basis for receptor affinity.,Clackson T, Ultsch MH, Wells JA, de Vos AM J Mol Biol. 1998 Apr 17;277(5):1111-28. PMID:9571026[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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