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The crystal structure of affinity-matured human growth hormone at 2 A resolution.

Abstract：

: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.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Ultsch MH,Somers W,Kossiakoff AA,de Vos AM

doi

10.1006/jmbi.1994.1135

subject

Has Abstract

pub_date

1994-02-11 00:00:00

pages

286-99

issue

1

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(84)71135-1

journal_volume

236

pub_type

杂志文章

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