1KF9

PHAGE DISPLAY DERIVED VARIANT OF HUMAN GROWTH HORMONE COMPLEXED WITH TWO COPIES OF THE EXTRACELLULAR DOMAIN OF ITS RECEPTOR

Summary for 1KF9

• Entry DOI: 10.2210/pdb1kf9/pdb
• Descriptor: PHAGE DISPLAY DERIVED VARIANT HUMAN GROWTH HORMONE, EXTRACELLULAR DOMAIN HUMAN GROWTH HORMONE RECEPTOR (1-238) (3 entities in total)
• Functional Keywords: cytokine, hormone-receptor complex, phage display molecular plasticity, receptor homodimerization, human growth hormone, hormone-growth factor complex, hormone/growth factor
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 2: Cell membrane; Single-pass type I membrane protein. Growth hormone-binding protein: Secreted: P10912
• Total number of polymer chains: 6
• Total formula weight: 153612.34

Authors

Schiffer, C.A.,Ultsch, M.,Walsh, S.,Somers, W.,De Vos, A.M.,Kossiakoff, A.A. (deposition date: 2001-11-19, release date: 2002-11-20, Last modification date: 2024-10-16)

Primary citation

Schiffer, C.A.,Ultsch, M.,Walsh, S.,Somers, W.,De Vos, A.M.,Kossiakoff, A.A.
Structure of a Phage Display Derived Variant of Human Growth Hormone Complexed to Two Copies of the Extracellular Domain of its Receptor: Evidence for Strong Structural Coupling between Receptor Binding Sites
J.Mol.Biol., 316:277-289, 2002

PubMed Abstract: The structure of the ternary complex between the phage display- optimized, high-affinity Site 1 variant of human growth hormone (hGH) and two copies of the extracellular domain (ECD) of the hGH receptor (hGHR) has been determined at 2.6 A resolution. There are widespread and significant structural differences compared to the wild-type ternary hGH hGHR complex. The hGH variant (hGH(v)) contains 15 Site 1 mutations and binds>10(2) tighter to the hGHR ECD (hGH(R1)) at Site 1. It is biologically active and specific to hGHR. The hGH(v) Site 1 interface is somewhat smaller and 20% more hydrophobic compared to the wild-type (wt) counterpart. Of the ten hormone-receptor H-bonds in the site, only one is the same as in the wt complex. Additionally, several regions of hGH(v) structure move up to 9A in forming the interface. The contacts between the C-terminal domains of two receptor ECDs (hGH(R1)- hGH(R2)) are conserved; however, the large changes in Site 1 appear to cause global changes in the domains of hGH(R1) that affect the hGH(v)-hGH(R2) interface indirectly. This coupling is manifested by large changes in the conformation of groups participating in the Site 2 interaction and results in a structure for the site that is reorganized extensively. The hGH(v)- hGH(R2) interface contains seven H-bonds, only one of which is found in the wt complex. Several groups on hGH(v) and hGH(R2) undergo conformational changes of up to 8 A. Asp116 of hGH(v) plays a central role in the reorganization of Site 2 by forming two new H-bonds to the side-chains of Trp104(R2) and Trp169(R2), which are the key binding determinants of the receptor. The fact that a different binding solution is possible for Site 2, where there were no mutations or binding selection pressures, indicates that the structural elements found in these molecules possess an inherent functional plasticity that enables them to bind to a wide variety of binding surfaces.

PubMed: 11851338
DOI: 10.1006/jmbi.2001.5348

Experimental method

X-RAY DIFFRACTION (2.6 Å)