1a22

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spinqualitylabelsall models 1a22, resolution 2.6Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

HUMAN GROWTH HORMONE BOUND TO SINGLE RECEPTOR

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The 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.

Disease

Known diseases associated with this structure: Growth hormone deficiency OMIM:[139250], Growth hormone deficiency, isolated, type IA OMIM:[139250], Growth hormone deficiency, isolated, type IB OMIM:[139250], Growth hormone deficiency, isolated, type II OMIM:[139250], Increased responsiveness to growth hormone OMIM:[600946], Kowarski syndrome OMIM:[139250], Laron dwarfism OMIM:[600946], Short stature, autosomal dominant, with normal serum growth hormone binding protein OMIM:[600946], Short stature, familial OMIM:[139250], Short stature, idiopathic OMIM:[600946]

About this Structure

1A22 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

Reference

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

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