PDBsum entry 1z7c

Hormone/growth factor

PDB id: 1z7c

Contents

Protein chain

161 a.a. *

Waters ×65

* Residue conservation analysis

PDB id:

1z7c

Name:

Hormone/growth factor

Title:

Crystal structure of human placental lactogen

Structure:

Chorionic somatomammotropin hormone. Chain: a. Synonym: choriomammotropin, lactogen. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: csh1. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.

Biol. unit:

Dimer (from PQS)

Resolution:

2.00Å R-factor: 0.233 R-free: 0.267

Authors:

S.T.R.Walsh,A.A.Kossiakoff

Key ref:

S.T.Walsh and A.A.Kossiakoff (2006). Crystal structure and site 1 binding energetics of human placental lactogen. J Mol Biol, 358, 773-784. PubMed id: 16546209 DOI: 10.1016/j.jmb.2006.02.038

Date:

24-Mar-05 Release date: 07-Mar-06

Protein chain

P0DML2  (CSH1_HUMAN) -  Chorionic somatomammotropin hormone 1 from Homo sapiens

Seq: 217 a.a.

Struc: 161 a.a.

DOI no: 10.1016/j.jmb.2006.02.038

J Mol Biol 358:773-784 (2006)

PubMed id: 16546209

Crystal structure and site 1 binding energetics of human placental lactogen.

S.T.Walsh, A.A.Kossiakoff.

ABSTRACT

In primates, placental lactogen (PL) is a pituitary hormone with fundamental roles during pregnancy involving fetal growth, metabolism, and stimulating lactation in the mother. Human placental lactogen (hPL) is highly conserved with human growth hormone (hGH) and both hormones bind to the hPRLR extracellular domain (ECD), the first step in receptor homodimerization, in a Zn2+-dependent manner. A modified surface plasmon resonance method was developed to measure the kinetics for hPL and hGH binding to the hPRLR ECD, with and without Zn2+ and showed that hPL has about a tenfold higher affinity for the hPRLR ECD1 than hGH. The crystal structure of the free state of hPL has been determined to 2.0 A resolution showing the molecule possesses an overall structure similar to other long chain four-helix bundle cytokines. Comparison of the free hPL structure with the 1:1 complex structure of hGH bound to the hPRLR ECD1 suggests that two surface loops undergo conformational changes >10 A upon binding. An 18 residue Ala-scan was used to characterize the binding energy epitope for the site 1 interface of hPL. Individual alanine substitutions at five positions reduced binding affinity by a DeltaDeltaG > or = 3 kcal mol(-1). A comparison of the hPL site 1 epitope with that previously determined for hGH indicates contributions of individual residues track reasonably well between hPL and hGH. In particular, residues involved in the zinc-binding site and Lys172 constitute the principal binding determinants for both hormones. However, several residues that are identical between hPL and hGH contribute quite differently to the binding of the hPRLR ECD1. Additionally, the overall magnitudes of the DeltaDeltaG changes observed from the Ala-scan of hPL were markedly larger than those determined in the comparative scan of hGH to the hPRLR ECD1. The structural and biophysical data presented here show that subtle changes in the structural context of an interaction can lead to significantly different effects at the individual residue level.

Selected figure(s)

Figure 2.
Figure 2. Backbone superimposition of hPL (red tube) onto the structure of hGH (white tube) from the 1:1 complex of hGH bound to the extracellular domain of the prolactin receptor (1bp3.pdb).^14 The structure of ovine placental lactogen (oPL, cyan tube) from the ternary complex of oPL bound to two copies of the rat prolactin receptor ECD is also superimposed onto the hGH structure (1f6f.pdb).^13 The regions that show the most significant changes between the structures are circled and involve residues in the 60s and 100s loop regions. Helices 1 through 4 are labeled accordingly.

Figure 3.
Figure 3. Site 1 binding kinetics of wt-hPL interacting with the immobilized hPRLR ECD1 measured by surface plasmon resonance at 25 °C. The residuals are plotted above the binding sensorgrams.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2006, 358, 773-784) copyright 2006.

Figures were selected by an automated process.